The present invention is in the field of medicinal chemistry and relates to compounds that are protein kinase inhibitors, compositions containing such compounds and methods of use. More particularly, this invention relates to compounds that are inhibitors of Aurora-2 protein kinase. The invention also relates to methods of treating diseases associated with protein kinases, especially diseases associated with Aurora-2, such as cancer.
The search for new therapeutic agents has been greatly aided in recent years by better understanding of the structure of enzymes and other biomolecules associated with target diseases. One important class of enzymes that has been the subject of extensive study is the protein kinases.
Protein kinases mediate intracellular signal transduction. They do this by effecting a phosphoryl transfer from a nucleoside triphosphate to a protein acceptor that is involved in a signaling pathway. There are a number of kinases and pathways through which extracellular and other stimuli cause a variety of cellular responses to occur inside the cell. Examples of such stimuli include environmental and chemical stress signals (e.g. osmotic shock, heat shock, ultraviolet radiation, bacterial endotoxin, H2O2), cytokines (e.g. interleukin-1 (IL-1) and tumor necrosis factor xcex1 (TNF-xcex1)), and growth factors (e.g. granulocyte macrophage-colony-stimulating factor (GM-CSF), and fibroblast growth factor (FGF). An extracellular stimulus may effect one or more cellular responses related to cell growth, migration, differentiation, secretion of hormones, activation of transcription factors, muscle contraction, glucose metabolism, control of protein synthesis and regulation of cell cycle.
Many diseases are associated with abnormal cellular responses triggered by protein kinase-mediated events. These diseases include autoimmune diseases, inflammatory diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer""s disease or hormone-related diseases. Accordingly, there has been a substantial effort in medicinal chemistry to find protein kinase inhibitors that are effective as therapeutic agents.
Aurora-2 is a serine/threonine protein kinase that has been implicated in human cancer, such as colon, breast and other solid tumors. This kinase is believed to be involved in protein phosphorylation events that regulate the cell cycle. Specifically, Aurora-2 may play a role in controlling the accurate segregation of chromosomes during mitosis. Misregulation of the cell cycle can lead to cellular proliferation and other abnormalities. In human colon cancer tissue, the aurora-2 protein has been found to be overexpressed. See Bischoff et al., EMBO J., 1998, 17, 3052-3065; Schumacher et al., J. Cell Biol., 1998, 143, 1635-1646; Kimura et al., J. Biol. Chem., 1997, 272, 13766-13771.
Glycogen synthase kinase-3 (GSK-3) is a serine/threonine protein kinase comprised of xcex1 and xcex2 isoforms that are each encoded by distinct genes [Coghlan et al., Chemistry and Biology, 7, 793-803 (2000); Kim and Kimmel, Curr. Opinion Genetics Dev., 10, 508-514 (2000)]. GSK-3 has been implicated in various diseases including diabetes, Alzheimer""s disease, CNS disorders such as manic depressive disorder and neurodegenerative diseases, and cardiomyocete hypertrophy [WO 99/65897; WO 00/38675; and Haq et al., J. Cell Biol. (2000) 151, 117]. These diseases may be caused by, or result in, the abnormal operation of certain cell signaling pathways in which GSK-3 plays a role. GSK-3 has been found to phosphorylate and modulate the activity of a number of regulatory proteins. These proteins include glycogen synthase which is the rate limiting enzyme necessary for glycogen synthesis, the microtubule associated protein Tau, the gene transcription factor xcex2-catenin, the translation initiation factor e1F2B, as well as ATP citrate lyase, axin, heat shock factor-1, c-Jun, c-Myc, c-Myb, CREB, and CEPBxcex1. These diverse protein targets implicate GSK-3 in many aspects of cellular metabolism, proliferation, differentiation and development.
In a GSK-3 mediated pathway that is relevant for the treatment of type II diabetes, insulin-induced signaling leads to cellular glucose uptake and glycogen synthesis. Along this pathway, GSK-3 is a negative regulator of the insulin-induced signal. Normally, the presence of insulin causes inhibition of GSK-3 mediated phosphorylation and deactivation of glycogen synthase. The inhibition of GSK-3 leads to increased glycogen synthesis and glucose uptake [Klein et al., PNAS, 93, 8455-9 (1996); Cross et al., Biochem. J., 303, 21-26 (1994); Cohen, Biochem. Soc. Trans., 21, 555-567 (1993); Massillon et al., Biochem J. 299, 123-128 (1994)]. However, in a diabetic patient where the insulin response is impaired, glycogen synthesis and glucose uptake fail to increase despite the presence of relatively high blood levels of insulin. This leads to abnormally high blood levels of glucose with acute and long term effects that may ultimately result in cardiovascular disease, renal failure and blindness. In such patients, the normal insulin-induced inhibition of GSK-3 fails to occur. It has also been reported that in patients with type II diabetes, GSK-3 is overexpressed [WO 00/38675]. Therapeutic inhibitors of GSK-3 are therefore potentially useful for treating diabetic patients suffering from an impaired response to insulin.
GSK-3 activity has also been associated with Alzheimer""s disease. This disease is characterized by the well-known xcex2-amyloid peptide and the formation of intracellular neurofibrillary tangles. The neurofibrillary tangles contain hyperphosphorylated Tau protein where Tau is phosphorylated on abnormal sites. GSK-3 has been shown to phosphorylate these abnormal sites in cell and animal models. Furthermore, inhibition of GSK-3 has been shown to prevent hyperphosphorylation of Tau in cells [Lovestone et al., Current Biology 4, 1077-86 (1994); Brownlees et al., Neuroreport 8, 3251-55 (1997)]. Therefore, it is believed that GSK-3 activity may promote generation of the neurofibrillary tangles and the progression of Alzheimer""s disease.
Another substrate of GSK-3 is xcex2-catenin which is degradated after phosphorylation by GSK-3. Reduced levels of xcex2-catenin have been reported in schizophrenic patients and have also been associated with other diseases related to increase in neuronal cell death [Zhong et al., Nature, 395, 698-702 (1998); Takashima et al., PNAS, 90, 7789-93 (1993); Pei et al., J. Neuropathol. Exp, 56, 70-78 (1997)].
As a result of the biological importance of GSK-3, there is current interest in therapeutically effective GSK-3 inhbitors. Small molecules that inhibit GSK-3 have recently been reported [WO 99/65897 (Chiron) and WO 00/38675 (SmithKline Beecham)].
For many of the aforementioned diseases associated with abnormal GSK-3 activity, other protein kinases have also been targeted for treating the same diseases. However, the various protein kinases often act through different biological pathways. For example, certain quinazoline derivatives have been reported recently as inhibitors of p38 kinase (WO 00/12497 to Scios). The compounds are reported to be useful for treating conditions characterized by enhanced p38-xcex1 activity and/or enhanced TGF-xcex2 activity. While p38 activity has been implicated in a wide variety of diseases, including diabetes, p38 kinase is not reported to be a constituent of an insulin signaling pathway that regulates glycogen synthesis or glucose uptake. Therefore, unlike GSK-3, p38 inhibition would not be expected to enhance glycogen synthesis and/or glucose uptake.
There is a continued need to find new therapeutic agents to treat human diseases. The protein kinases Aurora-2 and GSK-3 are especially attractive targets for the discovery of new therapeutics due to their important roles in cancer and diabetes, respectively.
It has now been found that compounds of this invention and pharmaceutical compositions thereof are effective as protein kinase inhibitors, particularly as inhibitors of Aurora-2. These compounds have the general formula I: 
or a pharmaceutically acceptable derivative or prodrug thereof, wherein:
Z1 to Z4 are as described below;
Ring A is selected from the group consisting of: 
Rx is Txe2x80x94R3 or Lxe2x80x94Zxe2x80x94R3;
Ry is Zxe2x80x94R3xe2x80x2 or an optionally substituted group selected from C1-6 aliphatic, C6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms, or Ry and R8 are taken together to form a fused, optionally substituted 5-7 membered, unsaturated or partially unsaturated, ring having 0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur;
Q is selected from xe2x80x94N(R4)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or xe2x80x94CH(R6)xe2x80x94;
R1 is T-(Ring D);
Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein each substitutable ring carbon of Ring D is independently substituted by oxo, Txe2x80x94R5, or Vxe2x80x94Zxe2x80x94R5, and each substitutable ring nitrogen of Ring D is independently substituted by xe2x80x94R4;
T is a valence bond or a C1-4 alkylidene chain, wherein when Q is xe2x80x94CH(R6)xe2x80x94, a methylene unit of said C1-4 alkylidene chain is optionally replaced by xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94N(R4)xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94CONHxe2x80x94, xe2x80x94NHCOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94SO2NHxe2x80x94, xe2x80x94NHSO2xe2x80x94, xe2x80x94CO2xe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94OC(O)NHxe2x80x94, or xe2x80x94NHCO2xe2x80x94;
Z is a C1-4 alkylidene chain;
L is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94N(R6)SO2xe2x80x94, xe2x80x94SO2N(R6)xe2x80x94, xe2x80x94N(R6)xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94CO2xe2x80x94, xe2x80x94N(R6)COxe2x80x94, xe2x80x94N(R6)C(O)Oxe2x80x94, xe2x80x94N(R6)CON(R6)xe2x80x94, xe2x80x94N(R6)SO2N(R6)xe2x80x94, xe2x80x94N(R6)N(R6)xe2x80x94, xe2x80x94C(O)N(R6)xe2x80x94, xe2x80x94OC(O)N(R6)xe2x80x94, xe2x80x94C(R6)2Oxe2x80x94, xe2x80x94C(R6)2Sxe2x80x94, xe2x80x94C(R6)2SOxe2x80x94, xe2x80x94C(R6)2SO2xe2x80x94, xe2x80x94C(R6)2SO2N(R6)xe2x80x94, xe2x80x94C(R6)2N(R6)xe2x80x94, xe2x80x94C(R6)2N(R6)C(O)xe2x80x94, xe2x80x94C(R6)2N(R6)C(O)Oxe2x80x94, xe2x80x94C(R6)xe2x95x90NN(R6)xe2x80x94, xe2x80x94C(R6)xe2x95x90Nxe2x80x94Oxe2x80x94, xe2x80x94C(R6)2N(R6)N(R6)xe2x80x94, xe2x80x94C(R6)2N(R6)SO2N(R6)xe2x80x94, or xe2x80x94C(R6)2N(R6)CON(R6)xe2x80x94;
R2 and R2xe2x80x2 are independently selected from xe2x80x94R, xe2x80x94Txe2x80x94Wxe2x80x94R6, or R2 and R2xe2x80x2 are taken together with their intervening atoms to form a fused, 5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, wherein each substitutable ring carbon of said fused ring formed by R2 and R2xe2x80x2 is independently substituted by halo, oxo, xe2x80x94CN, xe2x80x94NO2, xe2x80x94R7, or xe2x80x94Vxe2x80x94R6, and each substitutable ring nitrogen of said ring formed by R2 and R2xe2x80x2 is independently substituted by R4;
R3 is selected from xe2x80x94R, -halo, xe2x80x94OR, xe2x80x94C(xe2x95x90O)R, xe2x80x94CO2R, xe2x80x94COCOR, xe2x80x94COCH2COR, xe2x80x94NO2, xe2x80x94CN, xe2x80x94S(O)R, xe2x80x94S(O)2R, xe2x80x94SR, xe2x80x94N(R4)2, xe2x80x94CON(R7)2, xe2x80x94SO2N(R7)2, xe2x80x94OC(xe2x95x90O)R, xe2x80x94N(R7)COR, xe2x80x94N(R7)CO2(C1-6 aliphatic), xe2x80x94N(R4)N(R4)2, xe2x80x94Cxe2x95x90NN(R4)2, xe2x80x94Cxe2x95x90Nxe2x80x94OR, xe2x80x94N(R7)CON(R7)2, xe2x80x94N(R7)SO2N(R7)2, xe2x80x94N(R4)SO2R, or xe2x80x94OC(xe2x95x90O)N(R7 )2;
R3xe2x80x2 is selected from -halo, xe2x80x94OR, xe2x80x94C(xe2x95x90O)R, xe2x80x94CO2R, xe2x80x94COCOR, xe2x80x94COCH2COR, xe2x80x94NO2, xe2x80x94CN, xe2x80x94S(O)R, xe2x80x94S(O)2R, xe2x80x94SR, xe2x80x94N(R4)2, xe2x80x94CON(R7)2, xe2x80x94SO2N(R7)2, xe2x80x94OC(xe2x95x90O)R, xe2x80x94N(R7)COR, xe2x80x94N(R7)CO2(C1-6 aliphatic), xe2x80x94N(R4)N(R4)2, xe2x80x94Cxe2x95x90NN(R4)2, xe2x80x94Cxe2x95x90Nxe2x80x94OR, xe2x80x94N(R7)CON(R7)2, xe2x80x94N(R7)SO2N(R7)2, xe2x80x94N(R4)SO2R, xe2x80x94OC(xe2x95x90O)N(R7)2, or an optionally substituted group selected from C1-6 aliphatic, C6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms;
each R is independently selected from hydrogen or an optionally substituted group selected from C1-6 aliphatic, C6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms;
each R4 is independently selected from xe2x80x94R7, xe2x80x94COR7, xe2x80x94CO2 (optionally substituted C1-6 aliphatic), xe2x80x94CON(R7)2, or xe2x80x94SO2R7;
each R5 is independently selected from xe2x80x94R, halo, xe2x80x94OR, xe2x80x94C(xe2x95x90O)R, xe2x80x94CO2R, xe2x80x94COCOR, xe2x80x94NO2, xe2x80x94CN, xe2x80x94S(O)R, xe2x80x94SO2R, xe2x80x94SR, xe2x80x94N(R4)2, xe2x80x94CON(R4)2, xe2x80x94SO2N(R4)2, xe2x80x94OC(xe2x95x90O)R, xe2x80x94N(R4)COR, xe2x80x94N(R4)CO2 (optionally substituted C1-6 aliphatic), xe2x80x94N(R4)N(R4)2, xe2x80x94Cxe2x95x90NN(R4)2, xe2x80x94Cxe2x95x90Nxe2x80x94OR, xe2x80x94N(R4)CON(R4)2, xe2x80x94N(R4)SO2N(R4)2, xe2x80x94N(R4)SO2R, or xe2x80x94OC(xe2x95x90O)N(R4)2;
V is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94N(R6)SO2xe2x80x94, xe2x80x94SO2N(R6)xe2x80x94, xe2x80x94N(R6)xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94CO2xe2x80x94, xe2x80x94N(R6)COxe2x80x94, xe2x80x94N(R6)C(O)Oxe2x80x94, xe2x80x94N(R6)CON(R6)xe2x80x94, xe2x80x94N(R6)SO2N(R6)xe2x80x94, xe2x80x94N(R6)N(R6)xe2x80x94, xe2x80x94C(O)N(R6)xe2x80x94, xe2x80x94OC(O)N(R6)xe2x80x94, xe2x80x94C(R6)2Oxe2x80x94, xe2x80x94C(R6)2Sxe2x80x94, xe2x80x94C(R6)2SOxe2x80x94, xe2x80x94C(R6)2SO2xe2x80x94, xe2x80x94C(R6)2SO2N(R6)xe2x80x94, xe2x80x94C(R6)2N(R6)xe2x80x94, xe2x80x94C(R6)2N(R6)C(O)xe2x80x94, xe2x80x94C(R6)2N(R6)C(O)Oxe2x80x94, xe2x80x94C(R6)xe2x95x90NN(R6)xe2x80x94, xe2x80x94C(R6)xe2x95x90Nxe2x80x94Oxe2x80x94, xe2x80x94C(R6)2N(R6)N(R6)xe2x80x94, xe2x80x94C(R6)2N(R6)SO2N(R6)xe2x80x94, or xe2x80x94C(R6)2N(R6)CON(R6)xe2x80x94;
W is xe2x80x94C(R6)2Oxe2x80x94, xe2x80x94C(R6)2Sxe2x80x94, xe2x80x94C(R6)2SOxe2x80x94, xe2x80x94C(R6)2SO2xe2x80x94, xe2x80x94C(R6)2SO2N(R6)xe2x80x94, xe2x80x94C(R6)2N(R6)xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94CO2xe2x80x94, xe2x80x94C(R6)OC(O)xe2x80x94, xe2x80x94C(R6)OC(O)N(R6)xe2x80x94, xe2x80x94C(R6)2N(R6)COxe2x80x94, xe2x80x94C(R6)2N(R6)C(O)Oxe2x80x94, xe2x80x94C(R6)xe2x95x90NN(R6)xe2x80x94, xe2x80x94C(R6)xe2x95x90Nxe2x80x94Oxe2x80x94, xe2x80x94C(R6)2N(R6)N(R6)xe2x80x94, xe2x80x94C(R6)2N(R6)SO2N(R6)xe2x80x94, xe2x80x94C(R6)2N(R6)CON(R6)xe2x80x94, or xe2x80x94CON(R6)xe2x80x94;
each R6 is independently selected from hydrogen or an optionally substituted C1-4 aliphatic group, or two R6 groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring;
each R7 is independently selected from hydrogen or an optionally substituted C1-6 aliphatic group, or two R7 on the same nitrogen are taken together with the nitrogen-to form a 5-8 membered heterocyclyl or heteroaryl ring; and
R8 is selected from xe2x80x94R, halo, xe2x80x94OR, xe2x80x94C(xe2x95x90O)R, xe2x80x94CO2R, xe2x80x94COCOR, xe2x80x94NO2, xe2x80x94CN, xe2x80x94S(O)R, xe2x80x94SO2R, xe2x80x94SR, xe2x80x94N(R4)2, xe2x80x94CON(R4)2, xe2x80x94SO2N(R4)2, xe2x80x94OC(xe2x95x90O)R, xe2x80x94N(R4)COR, xe2x80x94N(R4)CO2 (optionally substituted C1-6 aliphatic), xe2x80x94N(R4)N(R4)2, xe2x80x94Cxe2x95x90NN(R4)2, xe2x80x94Cxe2x95x90Nxe2x80x94OR, xe2x80x94N(R4)CON(R4)2, xe2x80x94N(R4)SO2N(R4)2, xe2x80x94N(R4)SO2R, or xe2x80x94OC(xe2x95x90O)N R4)2.
As used herein, the following definitions shall apply unless otherwise indicated. The phrase xe2x80x9coptionally substitutedxe2x80x9d is used interchangeably with the phrase xe2x80x9csubstituted or unsubstitutedxe2x80x9d or with the term xe2x80x9c(un)substituted.xe2x80x9d Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and each substitution is independent of the other.
The term xe2x80x9caliphaticxe2x80x9d as used herein means straight-chain, branched or cyclic C1-C12 hydrocarbons which are completely saturated or which contain one or more units of unsaturation but which are not aromatic. For example, suitable aliphatic groups include substituted or unsubstituted linear, branched or cyclic alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl. The terms xe2x80x9calkylxe2x80x9d, xe2x80x9calkoxyxe2x80x9d, xe2x80x9chydroxyalkylxe2x80x9d, xe2x80x9calkoxyalkylxe2x80x9d, and xe2x80x9calkoxycarbonylxe2x80x9d, used alone or as part of a larger moiety includes both straight and branched chains containing one to twelve carbon atoms. The terms xe2x80x9calkenylxe2x80x9d and xe2x80x9calkynylxe2x80x9d used alone or as part of a larger moiety shall include both straight and branched chains containing two to twelve carbon atoms. The term xe2x80x9ccycloalkylxe2x80x9d used alone or as part of a larger moiety shall include cyclic C3-C12 hydrocarbons which are completely saturated or which contain one or more units of unsaturation, but which are not aromatic.
The terms xe2x80x9chaloalkylxe2x80x9d, xe2x80x9chaloalkenylxe2x80x9d and xe2x80x9chaloalkoxyxe2x80x9d means alkyl, alkenyl or alkoxy, as the case may be, substituted with one or more halogen atoms. The term xe2x80x9chalogenxe2x80x9d means F, Cl, Br, or I.
The term xe2x80x9cheteroatomxe2x80x9d means nitrogen, oxygen, or sulfur and includes any oxidized form of nitrogen and sulfur, and the quaternized form of any basic nitrogen. Also the term xe2x80x9cnitrogenxe2x80x9d includes a substitutable nitrogen of a heterocyclic ring. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+ (as in N-substituted pyrrolidinyl).
The terms xe2x80x9ccarbocyclexe2x80x9d, xe2x80x9ccarbocyclylxe2x80x9d, xe2x80x9ccarbocycloxe2x80x9d, or xe2x80x9ccarbocyclicxe2x80x9d as used herein means an aliphatic ring system having three to fourteen members. The terms xe2x80x9ccarbocyclexe2x80x9d, xe2x80x9ccarbocyclylxe2x80x9d, xe2x80x9ccarbocycloxe2x80x9d, or xe2x80x9ccarbocyclicxe2x80x9d whether saturated or partially unsaturated, also refers to rings that are optionally substituted. The terms xe2x80x9ccarbocyclexe2x80x9d, xe2x80x9ccarbocyclylxe2x80x9d, xe2x80x9ccarbocycloxe2x80x9d, or xe2x80x9ccarbocyclicxe2x80x9d also include aliphatic rings that are fused to one or more aromatic or nonaromatic rings, such as in a decahydronaphthyl or tetrahydronaphthyl, where the radical or point of attachment is on the aliphatic ring.
The term xe2x80x9carylxe2x80x9d used alone or as part of a larger moiety as in xe2x80x9caralkylxe2x80x9d, xe2x80x9caralkoxyxe2x80x9d, or xe2x80x9caryloxyalkylxe2x80x9d, refers to aromatic ring groups having five to fourteen members, such as phenyl, benzyl, phenethyl, 1-naphthyl, 2-naphthyl, 1-anthracyl and 2-anthracyl. The term xe2x80x9carylxe2x80x9d also refers to rings that are optionally substituted. The term xe2x80x9carylxe2x80x9d may be used interchangeably with the term xe2x80x9caryl ringxe2x80x9d. xe2x80x9cArylxe2x80x9d also includes fused polycyclic aromatic ring systems in which an aromatic ring is fused to one or more rings. Examples include 1-naphthyl, 2-naphthyl, 1-anthracyl and 2-anthracyl. Also included within the scope of the term xe2x80x9carylxe2x80x9d, as it is used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as in an indanyl, phenanthridinyl, or tetrahydronaphthyl, where the radical or point of attachment is on the aromatic ring.
The term xe2x80x9cheterocyclexe2x80x9d, xe2x80x9cheterocyclylxe2x80x9d, or xe2x80x9cheterocyclicxe2x80x9d as used herein includes non-aromatic ring systems having five to fourteen members, preferably five to ten, in which one or more ring carbons, preferably one to four, are each replaced by a heteroatom such as N, O, or S. Examples of heterocyclic rings include 3-1H-benzimidazol-2-one, (1-substituted)-2-oxo-benzimidazol-3-yl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl, [1,3]-dioxalanyl, [1,3]-dithiolanyl, [1,3]-dioxanyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl, 2-morpholinyl, 3-morpholinyl, 4-morpholinyl, 2-thiomorpholinyl, 3-thiomorpholinyl, 4-thiomorpholinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-piperazinyl, 2-piperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 4-thiazolidinyl, diazolonyl, N-substituted diazolonyl, 1-phthalimidinyl, benzoxanyl, benzopyrrolidinyl, benzopiperidinyl, benzoxolanyl, benzothiolanyl, and benzothianyl. Also included within the scope of the term xe2x80x9cheterocyclylxe2x80x9d or xe2x80x9cheterocyclicxe2x80x9d, as it is used herein, is a group in which a non-aromatic heteroatom-containing ring is fused to one or more aromatic or non-aromatic rings, such as in an indolinyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, where the radical or point of attachment is on the non-aromatic heteroatom-containing ring. The term xe2x80x9cheterocyclexe2x80x9d, xe2x80x9cheterocyclylxe2x80x9d, or xe2x80x9cheterocyclicxe2x80x9d whether saturated or partially unsaturated, also refers to rings that are optionally substituted.
The term xe2x80x9cheteroarylxe2x80x9d, used alone or as part of a larger moiety as in xe2x80x9cheteroaralkylxe2x80x9d or xe2x80x9cheteroarylalkoxyxe2x80x9d, refers to heteroaromatic ring groups having five to fourteen members. Examples of heteroaryl rings include 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxadiazolyl, 5-oxadiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 3-pyridazinyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 5-tetrazolyl, 2-triazolyl, 5-triazolyl, 2-thienyl, 3-thienyl, carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl, indolyl, quinolinyl, benzotriazolyl, benzothiazolyl, benzooxazolyl, benzimidazolyl, isoquinolinyl, indazolyl, isoindolyl, acridinyl, or benzoisoxazolyl. Also included within the scope of the term xe2x80x9cheteroarylxe2x80x9d, as it is used herein, is a group in which a heteroatomic ring is fused to one or more aromatic or nonaromatic rings where the radical or point of attachment is on the heteroaromatic ring. Examples include tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[3,4-d]pyrimidinyl. The term xe2x80x9cheteroarylxe2x80x9d also refers to rings that are optionally substituted. The term xe2x80x9cheteroarylxe2x80x9d may be used interchangeably with the term xe2x80x9cheteroaryl ringxe2x80x9d or the term xe2x80x9cheteroaromaticxe2x80x9d.
An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) or heteroaryl (including heteroaralkyl and heteroarylalkoxy and the like) group may contain one or more substituents. Examples of suitable substituents on the unsaturated carbon atom of an aryl, heteroaryl, aralkyl, or heteroaralkyl group include a halogen, xe2x80x94Ro, xe2x80x94ORo, xe2x80x94SRo, 1,2-methylene-dioxy, 1,2-ethylenedioxy, protected OH (such as acyloxy), phenyl (Ph), substituted Ph, xe2x80x94O(Ph), substituted xe2x80x94O(Ph), xe2x80x94CH2(Ph), substituted xe2x80x94CH2(Ph), xe2x80x94CH2CH2(Ph), substituted xe2x80x94CH2CH2(Ph), xe2x80x94NO2, xe2x80x94CN, xe2x80x94N(Ro)2, xe2x80x94NRoC(O)Ro, xe2x80x94NRoC(O)N(Ro)2, xe2x80x94NRoCO2Ro, xe2x80x94NRoNRoC(O)Ro, xe2x80x94NRoNRoC(O)N(Ro)2, xe2x80x94NRoNRoCO2Ro, xe2x80x94C(O)C(O)Ro, xe2x80x94C(O)CH2C(O)Ro, xe2x80x94CO2Ro, xe2x80x94C(O)Ro, xe2x80x94C(O)N(Ro)2, xe2x80x94OC(O)N(Ro)2, xe2x80x94S(O)2Ro, xe2x80x94SO2N(Ro)2, xe2x80x94S(O)Ro, xe2x80x94NRoSO2N(Ro)2, xe2x80x94NRoSO2Ro, xe2x80x94C(xe2x95x90S)N(Ro)2, xe2x80x94C(xe2x95x90NH)xe2x80x94N(Ro)2, xe2x80x94(CH2)yNHC(O)Ro, xe2x80x94(CH2)yNHC(O)CH(Vxe2x80x94Ro)(Ro); wherein Ro is hydrogen, a substituted or unsubstituted aliphatic group, an unsubstituted heteroaryl or heterocyclic ring, phenyl (Ph), substituted Ph, xe2x80x94O(Ph), substituted xe2x80x94O(Ph), xe2x80x94CH2(Ph), or substituted xe2x80x94CH2(Ph); y is 0-6; and V is a linker group. Examples of substituents on the aliphatic group or the phenyl ring of Ro include amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, haloalkoxy, or haloalkyl.
An aliphatic group or a non-aromatic heterocyclic ring may contain one or more substituents. Examples of suitable substituents on the saturated carbon of an aliphatic group or of a non-aromatic heterocyclic ring include those listed above for the unsaturated carbon of an aryl or heteroaryl group and the following: xe2x95x90O, xe2x95x90S, xe2x95x90NNHR*, xe2x95x90NN(R*)2, xe2x95x90Nxe2x80x94, xe2x95x90NNHC(O)R*, xe2x95x90NNHCO2(alkyl), xe2x95x90NNHSO2(alkyl), or xe2x95x90NR*, where each R* is independently selected from hydrogen, an unsubstituted aliphatic group or a substituted aliphatic group. Examples of substituents on the aliphatic group include amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, haloalkoxy, or haloalkyl.
Suitable substituents on the nitrogen of a non-aromatic heterocyclic ring include xe2x80x94R+, xe2x80x94N(R+)2, xe2x80x94C(O)R+, xe2x80x94CO2R+, xe2x80x94C(O)C(O)R+, xe2x80x94C(O)CH2C(O)R+, xe2x80x94SO2R+, xe2x80x94SO2N(R+)2, xe2x80x94C(xe2x95x90S)N(R+)2, xe2x80x94C(xe2x95x90NH)xe2x80x94N(R+)2, and xe2x80x94NR+SO2R+; wherein R+ is hydrogen, an aliphatic group, a substituted aliphatic group, phenyl (Ph), substituted Ph, xe2x80x94O(Ph), substituted xe2x80x94O(Ph), CH2(Ph), substituted CH2(Ph), or an unsubstituted heteroaryl or heterocyclic ring. Examples of substituents on the aliphatic group or the phenyl ring include amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, haloalkoxy, or haloalkyl.
The term xe2x80x9clinker groupxe2x80x9d or xe2x80x9clinkerxe2x80x9d means an organic moiety that connects two parts of a compound. Linkers are typically comprised of an atom such as oxygen or sulfur, a unit such as xe2x80x94NHxe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)NHxe2x80x94, or a chain of atoms, such as an alkylidene chain. The molecular mass of a linker is typically in the range of about 14 to 200, preferably in the range of 14 to 96 with a length of up to about six atoms. Examples of linkers include a saturated or unsaturated C1-6 alkylidene chain which is optionally substituted, and wherein one or two saturated carbons of the chain are optionally replaced by xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)C(O)xe2x80x94, xe2x80x94CONHxe2x80x94, xe2x80x94CONHNHxe2x80x94, xe2x80x94CO2xe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94NHCO2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94NHCONHxe2x80x94, xe2x80x94OC(O)NHxe2x80x94, xe2x80x94NHNHxe2x80x94, xe2x80x94NHCOxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94SO2NHxe2x80x94, or xe2x80x94NHSO2xe2x80x94.
The term xe2x80x9calkylidene chainxe2x80x9d refers to an optionally substituted, straight or branched carbon chain that may be fully saturated or have one or more units of unsaturation. The optional substituents are as described above for an aliphatic group.
A combination of substituents or variables is permissible only if such a combination results in a stable or chemically feasible compound. A stable compound or chemically feasible compound is one in which the chemical structure is not substantially altered when kept at a temperature of 40xc2x0 C. or less, in the absence of moisture or other chemically reactive conditions, for at least a week.
Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by a 13C- or 14C-enriched carbon are within the scope of this invention.
Compounds of formula I or salts thereof may be formulated into compositions. In a preferred embodiment, the composition is a pharmaceutical composition. In one embodiment, the composition comprises an amount of the protein kinase inhibitor effective to inhibit a protein kinase, particularly Aurora-2, in a biological sample or in a patient. In another embodiment, compounds of this invention and pharmaceutical compositions thereof, which comprise an amount of the protein kinase inhibitor effective to treat or prevent an Aurora-2-mediated condition and a pharmaceutically acceptable carrier, adjuvant, or vehicle, may be formulated for administration to a patient.
Another aspect of this invention relates to a method of treating or preventing an Aurora-2-mediated disease with an Aurora-2 inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula I or a pharmaceutical composition thereof.
The term xe2x80x9cAurora-2-mediated conditionxe2x80x9d or xe2x80x9cdiseasexe2x80x9d, as used herein, means any disease or other deleterious condition in which Aurora is known to play a role. The term xe2x80x9cAurora-2-mediated conditionxe2x80x9d or xe2x80x9cdiseasexe2x80x9d also means those diseases or conditions that are alleviated by treatment with an Aurora-2 inhibitor. Such conditions include, without limitation, cancer. The term xe2x80x9ccancerxe2x80x9d includes, but is not limited to the following cancers: colon, breast, stomach, and ovarian.
Another aspect of the invention relates to inhibiting Aurora-2 activity in a biological sample, which method comprises contacting the biological sample with the Aurora-2 inhibitor of formula I, or a composition thereof.
Another aspect of this invention relates to a method of inhibiting Aurora-2 activity in a patient, which method comprises administering to the patient a compound of formula I or a composition comprising said compound.
Another aspect of this invention relates to a method of treating or preventing a GSK-3-mediated disease with a GSK-3 inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula I or a pharmaceutical composition thereof.
The term xe2x80x9cGSK-3-mediated conditionxe2x80x9d or xe2x80x9cdiseasexe2x80x9d, as used herein, means any disease or other deleterious condition or state in which GSK-3 is known to play a role. Such diseases or conditions include, without limitation, diabetes, Alzheimer""s disease, Huntington""s Disease, Parkinson""s Disease, AIDS-associated dementia, amyotrophic lateral sclerosis (AML), multiple sclerosis (MS), schizophrenia, cardiomycete hypertrophy, reperfusion/ischemia, and baldness.
One aspect of this invention relates to a method of enhancing glycogen synthesis and/or lowering blood levels of glucose in a patient in need thereof, which method comprises administering to the patient a therapeutically effective amount of a compound of formula I or a pharmaceutical composition thereof. This method is especially useful for diabetic patients. Another method relates to inhibiting the production of hyperphosphorylated Tau protein, which is useful in halting or slowing the progression of Alzheimer""s disease. Another method relates to inhibiting the phosphorylation of xcex2-catenin, which is useful for treating schizophrenia.
Another aspect of the invention relates to inhibiting GSK-3 activity in a biological sample, which method comprises contacting the biological sample with a GSK-3 inhibitor of formula I.
Another aspect of this invention relates to a method of inhibiting GSK-3 activity in a patient, which method comprises administering to the patient a compound of formula I or a composition comprising said compound.
The term xe2x80x9cpharmaceutically acceptable carrier, adjuvant, or vehiclexe2x80x9d refers to a non-toxic carrier, adjuvant, or vehicle that may be administered to a patient, together with a compound of this invention, and which does not destroy the pharmacological activity thereof.
The term xe2x80x9cpatientxe2x80x9d includes human and veterinary subjects.
The term xe2x80x9cbiological samplexe2x80x9d, as used herein, includes, without limitation, cell cultures or extracts thereof; preparations of an enzyme suitable for in vitro assay; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.
The amount effective to inhibit protein kinase, for example, Aurora-2 and GSK-3, is one that measurably inhibits the kinase activity where compared to the activity of the enzyme in the absence of an inhibitor. Any method may be used to determine inhibition, such as, for example, the Biological Testing Examples described below.
Pharmaceutically acceptable carriers that may be used in these pharmaceutical compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
The compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term xe2x80x9cparenteralxe2x80x9d as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously.
Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer""s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
The pharmaceutical compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
Alternatively, the pharmaceutical compositions of this invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.
The pharmaceutical compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.
For topical applications, the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
For ophthalmic use, the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutical compositions may be formulated in an ointment such as petrolatum.
The pharmaceutical compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
In addition to the compounds of this invention, pharmaceutically acceptable derivatives or prodrugs of the compounds of this invention may also be employed in compositions to treat or prevent the above-identified diseases or disorders.
A xe2x80x9cpharmaceutically acceptable derivative or prodrugxe2x80x9d means any pharmaceutically acceptable salt, ester, salt of an ester or other derivative of a compound of this invention which, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof. Particularly favored derivatives or prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a patient (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to the parent species.
Pharmaceutically acceptable prodrugs of the compounds of this invention include, without limitation, esters, amino acid esters, phosphate esters, metal salts and sulfonate esters.
Pharmaceutically acceptable salts of the compounds of this invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acid salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, tosylate and undecanoate. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.
Salts derived from appropriate bases include alkali metal (e.g., sodium and potassium), alkaline earth metal (e.g., magnesium), ammonium and N+(C1-4 alkyl)4 salts. This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quaternization.
The amount of the protein kinase inhibitor that may be combined with the carrier materials to produce a single dosage form will vary depending upon the patient treated and the particular mode of administration. Preferably, the compositions should be formulated so that a dosage of between 0.01-100 mg/kg body weight/day of the inhibitor can be administered to a patient receiving these compositions.
It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of the inhibitor will also depend upon the particular compound in the composition.
Depending upon the particular protein kinase-mediated condition to be treated or prevented, additional therapeutic agents, which are normally administered to treat or prevent that condition, may be administered together with the inhibitors of this invention. For example, in the treatment of cancer other chemotherapeutic agents or other anti-proliferative agents may be combined with the Aurora-2 inhibitors of this invention to treat cancer. These agents include, without limitation, adriamycin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, taxol, interferons, and platinum derivatives.
Other examples of agents the inhibitors of this invention may also be combined with include, without limitation, agents for treating diabetes such as insulin or insulin analogues, in injectable or inhalation form, glitazones, alpha glucosidase inhibitors, biguanides, insulin sensitizers, and sulfonyl ureas; anti-inflammatory agents such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulatory and immunosuppressive agents such as cyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophophamide, azathioprine, and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anti-convulsants, ion channel blockers, riluzole, and anti-Parkinsonian agents; agents for treating cardiovascular disease such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; agents for treating liver disease such as corticosteroids, cholestyramine, interferons, and anti-viral agents; agents for treating blood disorders such as corticosteroids, anti-leukemic agents, and growth factors; and agents for treating immunodeficiency disorders such as gamma globulin.
Those additional agents may be administered separately from the protein kinase inhibitor-containing composition, as part of a multiple dosage regimen. Alternatively, those agents may be part of a single dosage form, mixed together with the protein kinase inhibitor of this invention in a single composition.
Compounds of this invention may exist in alternative tautomeric forms, as in tautomers i and ii shown below. Unless otherwise indicated, the representation of either tautomer is meant to include the other. 
Preferred Rx groups, when present, include hydrogen, alkyl- or dialkylamino, acetamido, or a C1-4 aliphatic group such as methyl, ethyl, cyclopropyl, or isopropyl.
Preferred Ry groups, when present, include Zxe2x80x94R3xe2x80x2 or an optionally substituted group selected from C1-6 aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, wherein Z is a methylene and R3xe2x80x2 is xe2x80x94N(R4)2, xe2x80x94OR, or an optionally substituted group selected from C1-6 aliphatic, C6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms. Preferred Ry groups include 5-6 membered heteroaryl or heterocyclyl rings, such as 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, or piperazinyl; C1-6 aliphatic, such as methyl, ethyl, cyclopropyl, isopropyl, or t-butyl; alkoxyalkylamino such as methoxyethylamino;, alkoxyalkyl such as methoxymethyl or methoxyethyl; alkyl- or dialkylamino such as ethylamino or dimethylamino; alkyl- or dialkylaminoalkoxy such as dimethylaminopropyloxy; acetamido; and optionally substituted phenyl such as phenyl or halo-substituted phenyl.
R2 and R2xe2x80x2 may be taken together to form a fused ring, thus providing a bicyclic ring system containing a pyrazole ring. Preferred fused rings include benzo, pyrido, pyrimido, and a partially unsaturated 6-membered carbocyclo ring, wherein said fused ring is optionally substituted. These are exemplified in the following formula I compounds having a pyrazole-containing bicyclic ring system: 
Preferred substituents on the R2/R2xe2x80x2 fused ring include one or more of the following: -halo, xe2x80x94N(R4)2, xe2x80x94C1-3 alkyl, xe2x80x94C1-3 haloalkyl, xe2x80x94NO2, xe2x80x94O(C1-3 alkyl), xe2x80x94CO2(C1-3 alkyl), xe2x80x94CN, xe2x80x94SO2(C1-3 alkyl), xe2x80x94SO2NH2, xe2x80x94OC(O)NH2, xe2x80x94NH2SO2(C1-3 alkyl), xe2x80x94NHC(O)(C1-3 alkyl), xe2x80x94C(O)NH2, and xe2x80x94CO(C1-3 alkyl), wherein the (C1-3 alkyl) is most preferably methyl.
When the pyrazole ring system is monocyclic, preferred R2 groups include hydrogen, C1-4 aliphatic, alkoxycarbonyl, (un)substituted phenyl, hydroxyalkyl, alkoxyalkyl, aminocarbonyl, mono- or dialkylaminocarbonyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, phenylaminocarbonyl, and (N-heterocyclyl)carbonyl. Examples of such preferred R2 substituents include methyl, cyclopropyl, ethyl, isopropyl, propyl, t-butyl, cyclopentyl, phenyl, CO2H, CO2CH3, CH2OH, CH2OCH3, CH2CH2CH2OH, CH2CH2CH2OCH3, CH2CH2CH2OCH2Ph, CH2CH2CH2NH2, CH2CH2CH2NHCOOC(CH3)3, CONHCH(CH3)2, CONHCH2CHxe2x95x90CH2, CONHCH2CH2OCH3, CONHCH2Ph, CONH(cyclohexyl), CON(Et)2, CON(CH3)CH2Ph, CONH(n-C3H7), CON(Et)CH2CH2CH3, CONHCH2CH(CH3)2, CON(n-C3H7)2, CO(3-methoxymethylpyrrolidin-1-yl), CONH(3-tolyl), CONH(4-tolyl), CONHCH3, CO(morpholin-1-yl), CO(4-methylpiperazin-1-yl), CONHCH2CH2OH, CONH2, and CO(piperidin-1-yl). A preferred R2xe2x80x2 group is hydrogen.
Preferred Q groups of formula I include xe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94, and xe2x80x94CH2xe2x80x94. More preferred Q groups of formula I include xe2x80x94Sxe2x80x94 and xe2x80x94NHxe2x80x94.
Another embodiment of this invention relates to compounds of formula II: 
or a pharmaceutically acceptable derivative or prodrug thereof, wherein:
Z1 is nitrogen or CR8;
Ry is Zxe2x80x94R3xe2x80x2 or an optionally substituted group selected from C1-6 aliphatic, C6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms, or Ry and R8 are taken together to form a fused, optionally substituted 5-7 membered, unsaturated or partially unsaturated, ring having 0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur;
Q is selected from xe2x80x94N(R4)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or xe2x80x94CH(R6)xe2x80x94;
R1 is T-(Ring D);
Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein each substitutable ring carbon of Ring D is independently substituted by oxo, Txe2x80x94R5, or Vxe2x80x94Zxe2x80x94R5, and each substitutable ring nitrogen of Ring D is independently substituted by xe2x80x94R4;
T is a valence bond or a C1-4 alkylidene chain, wherein when Q is xe2x80x94CH(R6)xe2x80x94, a methylene unit of said C1-4 alkylidene chain is optionally replaced by xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94N(R4)xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94CONHxe2x80x94, xe2x80x94NHCOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94SO2NHxe2x80x94, xe2x80x94NHSO2xe2x80x94, xe2x80x94CO2xe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94OC(O)NHxe2x80x94, or xe2x80x94NHCO2xe2x80x94;
Z is a C1-4 alkylidene chain;
L is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94N(R6)SO2xe2x80x94, xe2x80x94SO2N(R6)xe2x80x94, xe2x80x94N(R6)xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94CO2xe2x80x94, xe2x80x94N(R6)COxe2x80x94, xe2x80x94N(R6)C(O)Oxe2x80x94, xe2x80x94N(R6)CON(R6)xe2x80x94, xe2x80x94N(R6)SO2N(R6)xe2x80x94, xe2x80x94N(R6)N(R6)xe2x80x94, xe2x80x94C(O)N(R6)xe2x80x94, xe2x80x94OC(O)N(R6)xe2x80x94, xe2x80x94C(R6)2Oxe2x80x94, xe2x80x94C(R6)2Sxe2x80x94, xe2x80x94C(R6)2SOxe2x80x94, xe2x80x94C(R6)2SO2xe2x80x94, xe2x80x94C(R6)2SO2N(R6)xe2x80x94, xe2x80x94C(R6)2N(R6)xe2x80x94, xe2x80x94C(R6)2N(R6)C(O)xe2x80x94, xe2x80x94C(R6)2N(R6)C(O)Oxe2x80x94, xe2x80x94C(R6)xe2x95x90NN(R6)xe2x80x94, xe2x80x94C(R6)xe2x95x90Nxe2x80x94Oxe2x80x94, xe2x80x94C(R6)2N(R6)N(R6)xe2x80x94, xe2x80x94C(R6)2N(R6)SO2N(R6)xe2x80x94, or xe2x80x94C(R6)2N(R6)CON(R6)xe2x80x94;
R2 and R2xe2x80x2 are independently selected from xe2x80x94R, xe2x80x94Txe2x80x94Wxe2x80x94R6, or R2 and R2xe2x80x2 are taken together with their intervening atoms to form a fused, 5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, wherein each substitutable ring carbon of said fused ring formed by R2 and R2xe2x80x2 is independently substituted by halo, oxo, xe2x80x94CN, xe2x80x94NO2, xe2x80x94R7, or xe2x80x94Vxe2x80x94R6, and each substitutable ring nitrogen of said ring formed by R2 and R2xe2x80x2 is independently substituted by R4;
R3xe2x80x2 is selected from -halo, xe2x80x94OR, xe2x80x94C(xe2x95x90O)R, xe2x80x94CO2R, xe2x80x94COCOR, xe2x80x94COCH2COR, xe2x80x94NO2, xe2x80x94CN, xe2x80x94S(O)R, xe2x80x94S(O)2R, xe2x80x94SR, xe2x80x94N(R4)2, xe2x80x94CON(R7)2, xe2x80x94SO2N(R7)2, xe2x80x94OC(xe2x95x90O)R, xe2x80x94N(R7)COR, xe2x80x94N(R7)CO2(C1-6 aliphatic), xe2x80x94N(R4)N(R4)2, xe2x80x94Cxe2x95x90NN(R4)2, xe2x80x94Cxe2x95x90Nxe2x80x94OR, xe2x80x94N(R7)CON(R7)2, xe2x80x94N(R7)SO2N(R7)2, xe2x80x94N(R4)SO2R, xe2x80x94OC(xe2x95x90O)N(R7)2, or an optionally substituted group selected from C1-6 aliphatic, C6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms;
each R is independently selected from hydrogen or an optionally substituted group selected from C1-6 aliphatic, C6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms;
each R4 is independently selected from xe2x80x94R7, xe2x80x94COR7, xe2x80x94CO2 (optionally substituted C1-6 aliphatic), xe2x80x94CON(R7)2, or xe2x80x94SO2R7;
each R5 is independently selected from xe2x80x94R, halo, xe2x80x94OR, xe2x80x94C(xe2x95x90O)R, xe2x80x94CO2R, xe2x80x94COCOR, xe2x80x94NO2, xe2x80x94CN, xe2x80x94S(O)R, xe2x80x94SO2R, xe2x80x94SR, xe2x80x94N(R4)2, xe2x80x94CON(R4)2, xe2x80x94SO2N(R4)2, xe2x80x94OC(xe2x95x90O)R, xe2x80x94N(R4)COR, xe2x80x94N(R4)CO2 (optionally substituted C1-6 aliphatic), xe2x80x94N(R4)N(R4)2, xe2x80x94Cxe2x95x90NN(R4)2, xe2x80x94Cxe2x95x90Nxe2x80x94OR, xe2x80x94N(R4)CON(R4)2, xe2x80x94N(R4)SO2N(R4)2, xe2x80x94N(R4)SO2R, or xe2x80x94OC(xe2x95x90O)N(R4)2;
V is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94N(R6)SO2xe2x80x94, xe2x80x94SO2N(R6)xe2x80x94, xe2x80x94N(R6)xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94CO2xe2x80x94, xe2x80x94N(R6)COxe2x80x94, xe2x80x94N(R6)C(O)Oxe2x80x94, xe2x80x94N(R6)CON(R6)xe2x80x94,xe2x80x94N(R6)SO2N(R6)xe2x80x94, xe2x80x94N(R6)N(R6)xe2x80x94, xe2x80x94C(O)N(R6)xe2x80x94, xe2x80x94OC(O)N(R6)xe2x80x94, xe2x80x94C(R6)2Oxe2x80x94, xe2x80x94C(R6)2Sxe2x80x94, xe2x80x94C(R6)2SOxe2x80x94, xe2x80x94C(R6)2SO2xe2x80x94, xe2x80x94C(R6)2SO2N(R6)xe2x80x94, xe2x80x94C(R6)2N(R6)xe2x80x94, xe2x80x94C(R6)2N(R6)C(O)xe2x80x94, xe2x80x94C(R6)2N(R6)C(O)Oxe2x80x94, xe2x80x94C(R6)xe2x95x90NN(R6)xe2x80x94, xe2x80x94C(R6)xe2x95x90Nxe2x80x94Oxe2x80x94, xe2x80x94C(R6)2N(R6)N(R6)xe2x80x94, xe2x80x94C(R6)2N(R6)SO2N(R6)xe2x80x94, or xe2x80x94C(R6)2N(R6)CON(R6)xe2x80x94;
W is xe2x80x94C(R6)2Oxe2x80x94, xe2x80x94C(R6)2Sxe2x80x94, xe2x80x94C(R6)2SOxe2x80x94, xe2x80x94C(R6)2SO2xe2x80x94, xe2x80x94C(R6)2SO2N(R6)xe2x80x94, xe2x80x94C(R6)2N(R6)xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94CO2xe2x80x94, xe2x80x94C(R6)OC(O)xe2x80x94, xe2x80x94C(R6)OC(O)N(R6)xe2x80x94, xe2x80x94C(R6)2N(R6)COxe2x80x94, xe2x80x94C(R6)2N(R6)C(O)Oxe2x80x94, xe2x80x94C(R6)xe2x95x90NN(R6)xe2x80x94, xe2x80x94C(R6)xe2x95x90Nxe2x80x94Oxe2x80x94, xe2x80x94C(R6)2N(R6)N(R6)xe2x80x94, xe2x80x94C(R6)2N(R6)SO2N(R6)xe2x80x94, xe2x80x94C(R6)2N(R6)CON(R6)xe2x80x94, or xe2x80x94CON(R6)xe2x80x94;
each R6 is independently selected from hydrogen or an optionally substituted C1-4 aliphatic group, or two R6 groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring;
each R7 is independently selected from hydrogen or an optionally substituted C1-6 aliphatic group, or two R7 on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring; and
R8 is selected from xe2x80x94R, halo, xe2x80x94OR, xe2x80x94C(xe2x95x90O)R, xe2x80x94CO2R, xe2x80x94COCOR, xe2x80x94NO2, xe2x80x94CN, xe2x80x94S(O)R, xe2x80x94SO2R, xe2x80x94SR, xe2x80x94N(R4)2, xe2x80x94CON(R4)2, xe2x80x94SO2N(R4)2, xe2x80x94OC(xe2x95x90O)R, xe2x80x94N(R4)COR, xe2x80x94N(R4)CO2(optionally substituted C1-6 aliphatic), xe2x80x94N(R4)N(R4)2, xe2x80x94Cxe2x95x90NN(R4)2, xe2x80x94Cxe2x95x90Nxe2x80x94OR, xe2x80x94N(R4)CON(R4)2, xe2x80x94N(R4)SO2N(R4)2, xe2x80x94N(R4)SO2R, or xe2x80x94OC(xe2x95x90O)N(R4)2; provided that when Q is xe2x80x94NHxe2x80x94 and Ry and R8 are taken together to form a fused ring, R1 is other than a pyrazol-3-yl ring or a pyrazol-3-yl-containing bicyclic ring system.
Another embodiment of this invention relates to compounds of formula IIa: 
or a pharmaceutically acceptable derivative or prodrug thereof, wherein:
Ry is Zxe2x80x94R3xe2x80x2 or an optionally substituted group selected from C1-6 aliphatic, C6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms;
Q is selected from xe2x80x94N(R4)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or xe2x80x94CH(R6)xe2x80x94;
R1 is T-(Ring D);
Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein each substitutable ring carbon of Ring D is independently substituted by oxo, Txe2x80x94R5, or Vxe2x80x94Zxe2x80x94R5, and each substitutable ring nitrogen of Ring D is independently substituted by xe2x80x94R4;
T is a valence bond or a C1-4 alkylidene chain, wherein when Q is xe2x80x94CH(R6)xe2x80x94, a methylene unit of said C1-4 alkylidene chain is optionally replaced by xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94N(R4)xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94CONHxe2x80x94, xe2x80x94NHCOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94SO2NHxe2x80x94, xe2x80x94NHSO2xe2x80x94, xe2x80x94CO2xe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94OC(O)NHxe2x80x94, or xe2x80x94NHCO2xe2x80x94;
Z is a C1-4 alkylidene chain;
L is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94N(R6)SO2xe2x80x94, xe2x80x94SO2N(R6)xe2x80x94, xe2x80x94N(R6)xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94CO2xe2x80x94, xe2x80x94N(R6)COxe2x80x94, xe2x80x94N(R6)C(O)Oxe2x80x94, xe2x80x94N(R6)CON(R6)xe2x80x94, xe2x80x94N(R6)SO2N(R6)xe2x80x94, xe2x80x94N(R6)N(R6)xe2x80x94, xe2x80x94C(O)N(R6)xe2x80x94, xe2x80x94OC(O)N(R6)xe2x80x94, xe2x80x94C(R6)2Oxe2x80x94, xe2x80x94C(R6)2Sxe2x80x94, xe2x80x94C(R6)2SOxe2x80x94, xe2x80x94C(R6)2SO2xe2x80x94, xe2x80x94C(R6)2SO2N(R6)xe2x80x94, xe2x80x94C(R6)2N(R6)xe2x80x94, xe2x80x94C(R6)2N(R6)C(O)xe2x80x94, xe2x80x94C(R6)2N(R6)C(O)Oxe2x80x94, xe2x80x94C(R6)xe2x95x90NN(R6)xe2x80x94, xe2x80x94C(R6)xe2x95x90Nxe2x80x94Oxe2x80x94, xe2x80x94C(R6)2N(R6)N(R6)xe2x80x94, xe2x80x94C(R6)2N(R6)SO2N(R6)xe2x80x94, or xe2x80x94C(R6)2N(R6)CON(R6)xe2x80x94;
R2 and R2xe2x80x2 are independently selected from xe2x80x94R, xe2x80x94Txe2x80x94Wxe2x80x94R or R2 and R2xe2x80x2 are taken together with their intervening atoms to form a fused, 5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, wherein each substitutable ring carbon of said fused ring formed by R2 and R2xe2x80x2 is independently substituted by halo, oxo, xe2x80x94CN, xe2x80x94NO2, xe2x80x94R7, or xe2x80x94Vxe2x80x94R6, and each substitutable ring nitrogen of said ring formed by R2 and R2xe2x80x2 is independently substituted by R4;
R3xe2x80x2 is selected from -halo, xe2x80x94OR, xe2x80x94C(xe2x95x90O)R, xe2x80x94CO2R, xe2x80x94COCOR, xe2x80x94COCH2COR, xe2x80x94NO2, xe2x80x94CN, xe2x80x94S(O)R, xe2x80x94S(O)2R, xe2x80x94SR, xe2x80x94N(R4)2, xe2x80x94CON(R7)2, xe2x80x94SO2N(R7)2, xe2x80x94OC(xe2x95x90O)R, xe2x80x94N(R7)COR, xe2x80x94N(R7)CO2(C1-6 aliphatic), xe2x80x94N(R4)N(R4)2, xe2x80x94Cxe2x95x90NN(R4)2, xe2x80x94Cxe2x95x90Nxe2x80x94OR, xe2x80x94N(R7)CON(R7)2, xe2x80x94N(R7)SO2N(R7)2, xe2x80x94N(R4)SO2R, xe2x80x94OC(xe2x95x90O)N(R7)2, or an optionally substituted group selected from C1-6 aliphatic, C6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms;
each R is independently selected from hydrogen or an optionally substituted group selected from C1-6 aliphatic, C1-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms;
each R4 is independently selected from xe2x80x94R7, xe2x80x94COR7, xe2x80x94CO2(optionally substituted C1-6 aliphatic), xe2x80x94CON(R7)2, or xe2x80x94SO2R7;
each R5 is independently selected from xe2x80x94R, halo, xe2x80x94OR, xe2x80x94C(xe2x95x90O)R, xe2x80x94CO2R, xe2x80x94COCOR, xe2x80x94NO2, xe2x80x94CN, xe2x80x94S(O)R, xe2x80x94SO2R, xe2x80x94SR, xe2x80x94N(R4)2, xe2x80x94CON(R4)2, xe2x80x94SO2N(R4)2, xe2x80x94OC(xe2x95x90O)R, xe2x80x94N(R4)COR, xe2x80x94N(R4)CO2(optionally substituted C1-6 aliphatic), xe2x80x94N(R4)N(R4)2, xe2x80x94Cxe2x95x90NN(R4)2, xe2x80x94Cxe2x95x90Nxe2x80x94OR, xe2x80x94N(R4)CON(R4)2, xe2x80x94N(R4)SO2N(R4)2, xe2x80x94N(R4)SO2R, or xe2x80x94OC(xe2x95x90O)N(R4)2;
V is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94N(R6)SO2xe2x80x94, xe2x80x94SO2N(R6)xe2x80x94, xe2x80x94N(R6)xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94CO2xe2x80x94, xe2x80x94N(R6)COxe2x80x94, xe2x80x94N(R6)C(O)Oxe2x80x94, xe2x80x94N(R6)CON(R6)xe2x80x94, xe2x80x94N(R6)SO2N(R6)xe2x80x94, xe2x80x94N(R6)N(R6)xe2x80x94, xe2x80x94C(O)N(R6)xe2x80x94, xe2x80x94OC(O)N(R6)xe2x80x94, xe2x80x94C(R6)2Oxe2x80x94, xe2x80x94C(R6)2Sxe2x80x94, xe2x80x94C(R6)2SOxe2x80x94, xe2x80x94C(R6)2SO2xe2x80x94, xe2x80x94C(R6)2SO2N(R6)xe2x80x94, xe2x80x94C(R6)2N(R6)xe2x80x94, xe2x80x94C(R6)2N(R6)C(O)xe2x80x94, xe2x80x94C(R6)2N(R6)C(O)Oxe2x80x94, xe2x80x94C(R6)xe2x95x90NN(R6)xe2x80x94, xe2x80x94C(R6)xe2x95x90Nxe2x80x94Oxe2x80x94, xe2x80x94C(R6)2N(R6)N(R6)xe2x80x94, C(R6)2N(R6)SO2N(R6)xe2x80x94, or xe2x80x94C(R6)2N(R6)CON(R6)xe2x80x94;
W is xe2x80x94C(R6)2Oxe2x80x94, xe2x80x94C(R6)2Sxe2x80x94, xe2x80x94C(R6)2SOxe2x80x94, xe2x80x94C(R6)2SO2xe2x80x94, xe2x80x94C(R6)2SO2N(R6)xe2x80x94, xe2x80x94C(R6)2N(R6)xe2x80x94, xe2x80x94COxe2x80x94, CO2xe2x80x94, xe2x80x94C(R6)OC(O)xe2x80x94, xe2x80x94C(R6)OC(O)N(R6)xe2x80x94, xe2x80x94C(R6)2N(R6)COxe2x80x94, xe2x80x94C(R6)2N(R6)C(O)Oxe2x80x94, xe2x80x94C(R6)xe2x95x90NN(R6)xe2x80x94, xe2x80x94C(R6)xe2x95x90Nxe2x80x94Oxe2x80x94, xe2x80x94C(R6)2N(R6)N(R6)xe2x80x94, xe2x80x94C(R6)2N(R6)SO2N(R6)xe2x80x94, xe2x80x94C(R6)2N(R6)CON(R6)xe2x80x94, or xe2x80x94CON(R6)xe2x80x94;
each R6 is independently selected from hydrogen or an optionally substituted C1-4 aliphatic group, or two R6 groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; and
each R7 is independently selected from hydrogen or an optionally substituted C1-6 aliphatic group, or two R7 on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring.
Preferred Ry groups of formula IIa include Zxe2x80x94R3xe2x80x2 or an optionally substituted group selected from C1-6 aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, wherein Z is a methylene and R3xe2x80x2 is xe2x80x94N(R4)2, xe2x80x94OR, or an optionally substituted group selected from C1-6 aliphatic, C6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms.
Examples of preferred Ry groups include 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino such as methoxyethylamino, alkoxyalkyl such as methoxymethyl or methoxyethyl, alkyl- or dialkylamino such as ethylamino or dimethylamino, alkyl- or dialkylaminoalkoxy such as dimethylaminopropyloxy, acetamido, optionally substituted phenyl such as phenyl or halo-substituted phenyl.
The R2 and R2xe2x80x2 groups of formula IIa may be taken together to form a fused ring, thus providing a bicyclic ring system containing a pyrazole ring. Preferred fused rings include benzo, pyrido, pyrimido, and a partially unsaturated 6-membered carbocyclo ring. These are exemplified in the following formula IIa compounds having a pyrazole-containing bicyclic ring system: 
Preferred substituents on the R2/R2xe2x80x2 fused ring of formula IIa include one or more of the following: -halo, xe2x80x94N(R4)2, xe2x80x94C1-4 alkyl, xe2x80x94C1-4 haloalkyl, xe2x80x94NO2, xe2x80x94O(C1-4 alkyl), xe2x80x94CO2(C1-4 alkyl), xe2x80x94CN, xe2x80x94SO2(C1-4 alkyl), xe2x80x94SO2NH2, xe2x80x94OC(O)NH2, xe2x80x94NH2SO2(C1-4 alkyl), xe2x80x94NHC(O)(C1-4 alkyl), xe2x80x94C(O)NH2, and xe2x80x94CO(C1-4 alkyl), wherein the (C1-4 alkyl) is a straight, branched, or cyclic alkyl group. Preferably, the (C1-4 alkyl) group is methyl.
When the pyrazole ring system of formula IIa is monocyclic, preferred R2 groups include hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a C1-6 aliphatic group. Examples of such preferred R2 groups include H, methyl, ethyl, propyl, cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, and benzyloxypropyl. A preferred R2xe2x80x2 group is hydrogen.
When Ring D of formula IIa is monocyclic, preferred Ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.
When Ring D of formula IIa is bicyclic, preferred bicyclic Ring D groups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl, indolyl, isoindolyl, indolinyl, benzo[b]furyl, benzo[b]thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl.
On Ring D of formula IIa, preferred Txe2x80x94R5 or Vxe2x80x94Zxe2x80x94R5 substituents include -halo, xe2x80x94CN, xe2x80x94NO2, xe2x80x94N(R4)2, optionally substituted C1-6 aliphatic group, xe2x80x94OR, xe2x80x94C(O)R, xe2x80x94CO2R, xe2x80x94CONH(R4), xe2x80x94N(R4)COR, xe2x80x94N(R4)CO2R, xe2x80x94SO2N(R4)2, xe2x80x94N(R4)SO2R, xe2x80x94N(R6)COCH2N(R4)2, xe2x80x94N(R6)COCH2CH2N(R4)2, and xe2x80x94N(R6)COCH2CH2CH2N(R4)2, wherein R is selected from hydrogen, C1-6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring. More preferred R5 substituents include xe2x80x94Cl, xe2x80x94Br, xe2x80x94F, xe2x80x94CN, xe2x80x94CF3, xe2x80x94COOH, xe2x80x94CONHMe, xe2x80x94CONHEt, xe2x80x94NH2, xe2x80x94NHAc, xe2x80x94NHSO2Me, xe2x80x94NHSO2Et, xe2x80x94NHSO2(n-propyl), xe2x80x94NHSO2(isopropyl), xe2x80x94NHCOEt, xe2x80x94NHCOCH2NHCH3, xe2x80x94NHCOCH2N(CO2t-Bu)CH3, xe2x80x94NHCOCH2N(CH3)2, xe2x80x94NHCOCH2CH2N(CH3)2, xe2x80x94NHCOCH2CH2CH2N(CH3)2, xe2x80x94NHCO(cyclopropyl), xe2x80x94NHCO(isobutyl), xe2x80x94NHCOCH2(morpholin-4-yl), xe2x80x94NHCOCH2CH2(morpholin-4-yl), xe2x80x94NHCOCH2CH2CH2(morpholin-4-yl), xe2x80x94NHCO2(t-butyl), xe2x80x94NH(C1-4 aliphatic) such as xe2x80x94NHMe, xe2x80x94N(C1-4 aliphatic)2 such as xe2x80x94NMe2, OH, xe2x80x94O(C1-4 aliphatic) such as xe2x80x94OMe, C1-4 aliphatic such as methyl, ethyl, cyclopropyl, isopropyl, or t-butyl, and xe2x80x94CO2(C1-4 aliphatic).
Preferred formula IIa compounds have one or more, and more preferably all, of the features selected from the group consisting of:
(a) Ry is Zxe2x80x94R3xe2x80x2 or an optionally substituted group selected from C1-6 aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, wherein Z is a methylene and R3xe2x80x2 is xe2x80x94N(R4)2, xe2x80x94OR, or an optionally substituted group selected from C1-6 aliphatic, C6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms;
(b) R1 is T-(Ring D), wherein T is a valence bond or a methylene unit;
(c) Ring D is a 5-7 membered monocyclic or an 8-10 membered bicyclic aryl or heteroaryl ring; and
(d) R2 is xe2x80x94R or xe2x80x94Txe2x80x94Wxe2x80x94R6 and R2xe2x80x2 is hydrogen, or R2 and R2xe2x80x2 are taken together to form an optionally substituted benzo ring.
More preferred compounds of formula IIa have one or more, and more preferably all, of the features selected from the group consisting of:
(a) Ry is an optionally substituted group selected from C1-6 aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl;
(b) R1 is T-(Ring D), wherein T is a valence bond and Q is xe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94, or xe2x80x94CH2xe2x80x94;
(c) Ring D is a 5-6 membered monocyclic or an 8-10 membered bicyclic aryl or heteroaryl ring; and
(d) R2 is xe2x80x94R and R2xe2x80x2 is hydrogen, wherein R is selected from hydrogen, C1-6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring.
Even more preferred compounds of formula IIa have one or more, and more preferably all, of the features selected from the group consisting of:
(a) Ry is selected from 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino, alkoxyalkyl, alkyl- or dialkylamino, alkyl- or dialkylaminoalkoxy, acetamido, optionally substituted phenyl, or methoxymethyl;
(b) R1 is T-(Ring D), wherein T is a valence bond and Ring D is a 5-6 membered aryl or heteroaryl ring, wherein Ring D is optionally substituted with one to two groups selected from -halo, xe2x80x94CN, xe2x80x94NO2, xe2x80x94N(R4)2, optionally substituted C1-6 aliphatic group, xe2x80x94OR, xe2x80x94CO2R, xe2x80x94CONH(R4), xe2x80x94N(R4)COR, xe2x80x94N(R4)SO2R, xe2x80x94N(R6)COCH2CH2N(R4)2, or xe2x80x94N(R6)COCH2CH2CH2N(R4)2, and Q is xe2x80x94Sxe2x80x94 or xe2x80x94NHxe2x80x94; and
(c) R2 is hydrogen or a substituted or unsubstituted C1-6 aliphatic, and L is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or xe2x80x94NHxe2x80x94.
Representative compounds of formula IIa are shown below in Table 1.
In another embodiment, this invention provides a composition comprising a compound of formula IIa and a pharmaceutically acceptable carrier.
Another aspect of this invention relates to a method of treating or preventing an Aurora-2-mediated disease with an Aurora-2 inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula IIa or a pharmaceutical composition thereof.
Another aspect of this invention relates to a method of inhibiting Aurora-2 activity in a patient, which method comprises administering to the patient a compound of formula IIa or a composition comprising said compound.
Another aspect of this invention relates to a method of treating or preventing a GSK-3-mediated disease with a GSK-3 inhibitor, which method comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula IIa or a pharmaceutical composition thereof.
One aspect of this invention relates to a method of enhancing glycogen synthesis and/or lowering blood levels of glucose in a patient in need thereof, which method comprises administering to the patient a therapeutically effective amount of a compound of formula IIa or a pharmaceutical composition thereof. This method is especially useful for diabetic patients. Another method relates to inhibiting the production of hyperphosphorylated Tau protein, which is useful in halting or slowing the progression of Alzheimer""s disease. Another method relates to inhibiting the phosphorylation of xcex2-catenin, which is useful for treating schizophrenia.
Another aspect of this invention relates to a method of inhibiting GSK-3 activity in a patient, which method comprises administering to the patient a compound of formula IIa or a composition comprising said compound.
Another method relates to inhibiting Aurora-2 or GSK-3 activity in a biological sample, which method comprises contacting the biological sample with the Aurora-2 or GSK-3 inhibitor of formula IIa, or a pharmaceutical composition thereof, in an amount effective to inhibit Aurora-2 or GSK-3.
Each of the aforementioned methods directed to the inhibition of Aurora-2 or GSK-3, or the treatment of a disease alleviated thereby, is preferably carried out with a preferred compound of formula IIa, as described above.
Another embodiment of this invention relates to compounds of formula IIb: 
or a pharmaceutically acceptable derivative or prodrug thereof, wherein:
Ry is Zxe2x80x94R3xe2x80x2 or an optionally substituted group selected from C1-6 aliphatic, C1-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms, or Ry and R8 are taken together to form a fused, optionally substituted 5-7 membered, unsaturated or partially unsaturated, ring having 0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur;
Q is selected from xe2x80x94N(R4)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or xe2x80x94CH(R6)xe2x80x94;
R1 is T-(Ring D)
Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein each substitutable ring carbon of Ring D is independently substituted by oxo, Txe2x80x94R5, or Vxe2x80x94Zxe2x80x94R5, and each substitutable ring nitrogen of Ring D is independently substituted by xe2x80x94R4;
T is a valence bond or a C1-4 alkylidene chain, wherein when Q is xe2x80x94CH(R6)xe2x80x94, a methylene unit of said C1-4 alkylidene chain is optionally replaced by xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94N(R4)xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94CONHxe2x80x94, xe2x80x94NHCOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94SO2NHxe2x80x94, xe2x80x94NHSO2xe2x80x94, xe2x80x94CO2xe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94OC(O)NHxe2x80x94, or xe2x80x94NHCO2xe2x80x94;
Z is a C1-4 alkylidene chain;
L is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94N(R6)SO2xe2x80x94, xe2x80x94SO2N(R6)xe2x80x94, xe2x80x94N(R6)xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94CO2xe2x80x94, xe2x80x94N(R6)COxe2x80x94, xe2x80x94N(R6)C(O)Oxe2x80x94, xe2x80x94N(R6)CON(R6)xe2x80x94, xe2x80x94N(R6)SO2N(R6)xe2x80x94, xe2x80x94N(R6)N(R6)xe2x80x94, xe2x80x94C(O)N(R6)xe2x80x94, xe2x80x94OC(O)N(R6)xe2x80x94, xe2x80x94C(R6)2Oxe2x80x94, xe2x80x94C(R6)2Sxe2x80x94, xe2x80x94C(R6)2SOxe2x80x94, xe2x80x94C(R6)2SO2xe2x80x94, xe2x80x94C(R6)2SO2N(R6)xe2x80x94, xe2x80x94C(R6)2N(R6)xe2x80x94, xe2x80x94C(R6)2N(R6)C(O)xe2x80x94, xe2x80x94C(R6)2N(R6)C(O)Oxe2x80x94, xe2x80x94C(R6)xe2x95x90NN(R6)xe2x80x94, xe2x80x94C(R6)xe2x95x90Nxe2x80x94Oxe2x80x94, xe2x80x94C(R6)2N(R6)N(R6)xe2x80x94, xe2x80x94C(R6)2N(R6)SO2N(R6)xe2x80x94, or xe2x80x94C(R6)2N(R6)CON(R6)xe2x80x94;
R2 and R2xe2x80x2 are independently selected from xe2x80x94R, xe2x80x94Txe2x80x94Wxe2x80x94R6, or R2 and R2xe2x80x2 are taken together with their intervening atoms to form a fused, 5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, wherein each substitutable ring carbon of said fused ring formed by R2 and R2xe2x80x2 is independently substituted by halo, oxo, xe2x80x94CN, xe2x80x94NO2, xe2x80x94R7, or xe2x80x94Vxe2x80x94R6, and each substitutable ring nitrogen of said ring formed by R2 and R2xe2x80x2 is independently substituted by R4;
R3xe2x80x2 is selected from -halo, xe2x80x94OR, xe2x80x94C(xe2x95x90O)R, xe2x80x94CO2R, xe2x80x94COCOR, xe2x80x94COCH2COR, xe2x80x94NO2, xe2x80x94CN, xe2x80x94S(O)R, xe2x80x94S(O)2R, xe2x80x94SR, xe2x80x94N(R4)2, xe2x80x94CON(R7)2, xe2x80x94SO2N(R7)2, xe2x80x94OC(xe2x95x90O)R, xe2x80x94N(R7)COR, xe2x80x94N(R7)CO2(C1-6 aliphatic), xe2x80x94N(R4)N(R4)2, xe2x80x94Cxe2x95x90NN(R4)2, xe2x80x94Cxe2x95x90Nxe2x80x94OR, xe2x80x94N(R7)CON(R7)2, xe2x80x94N(R7)SO2N(R7)2, xe2x80x94N(R4)SO2R, xe2x80x94OC(xe2x95x90O)N(R7)2, or an optionally substituted group selected from C1-6 aliphatic, C6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms;
each R is independently selected from hydrogen or an optionally substituted group selected from C1-6 aliphatic, C6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms;
each R4 is independently selected from xe2x80x94R7, xe2x80x94COR7, xe2x80x94CO2(optionally substituted C1-6 aliphatic), xe2x80x94CON(R7)2, or xe2x80x94SO2R7;
each R5 is independently selected from xe2x80x94R, halo, xe2x80x94OR, xe2x80x94C(xe2x95x90O)R, xe2x80x94CO2R, xe2x80x94COCOR, xe2x80x94NO2, xe2x80x94CN, xe2x80x94S(O)R, xe2x80x94SO2R, xe2x80x94SR, xe2x80x94N(R4)2, xe2x80x94CON(R4)2, xe2x80x94SO2N(R4)2, xe2x80x94OC(xe2x95x90O)R, xe2x80x94N(R4)COR, xe2x80x94N(R4)CO2(optionally substituted C1-6 aliphatic), xe2x80x94N(R4)N(R4)2, xe2x80x94Cxe2x95x90NN(R4)2, xe2x80x94Cxe2x95x90Nxe2x80x94OR, xe2x80x94N(R4)CON(R4)2, xe2x80x94N(R4)SO2N(R4)2, xe2x80x94N(R4)SO2R, or xe2x80x94OC(xe2x95x90O)N(R4)2;
V is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94N(R6)SO2xe2x80x94, xe2x80x94SO2N(R6)xe2x80x94, xe2x80x94N(R6)xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94CO2xe2x80x94, xe2x80x94N(R6)COxe2x80x94, xe2x80x94N(R6)C(O)Oxe2x80x94, xe2x80x94N(R6)CON(R6)xe2x80x94, xe2x80x94N(R6)SO2N(R6)xe2x80x94, xe2x80x94N(R6)N(R6)xe2x80x94, xe2x80x94C(O)N(R6)xe2x80x94, xe2x80x94OC(O)N(R6)xe2x80x94, xe2x80x94C(R6)2Oxe2x80x94, xe2x80x94C(R6)2Sxe2x80x94, xe2x80x94C(R6)2SOxe2x80x94, xe2x80x94C(R6)2SO2xe2x80x94, xe2x80x94C(R6)2SO2N(R6)xe2x80x94, xe2x80x94C(R6)2N(R6)xe2x80x94, xe2x80x94C(R6)2N(R6)C(O)xe2x80x94, xe2x80x94C(R6)2N(R6)C(O)Oxe2x80x94, xe2x80x94C(R6)xe2x95x90NN(R6)xe2x80x94, xe2x80x94C(R6)xe2x95x90Nxe2x80x94Oxe2x80x94, xe2x80x94C(R6)2N(R6)N(R6)xe2x80x94, xe2x80x94C(R6)2N(R6)SO2N(R6)xe2x80x94, or xe2x80x94C(R6)2N(R6)CON(R6)xe2x80x94;
W is xe2x80x94C(R6)2Oxe2x80x94, xe2x80x94C(R6)2Sxe2x80x94, xe2x80x94C(R6)2SOxe2x80x94, xe2x80x94C(R6)2SO2xe2x80x94, xe2x80x94C(R6)2SO2N(R6)xe2x80x94, xe2x80x94C(R6)2N(R6)xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94CO2xe2x80x94, xe2x80x94C(R6)OC(O)xe2x80x94, xe2x80x94C(R6)OC(O)N(R6)xe2x80x94, xe2x80x94C(R6)2N(R6)COxe2x80x94, xe2x80x94C(R6)2N(R6)C(O)Oxe2x80x94, C(R6)xe2x95x90NN(R6)xe2x80x94, xe2x80x94C(R6)xe2x95x90Nxe2x80x94Oxe2x80x94, xe2x80x94C(R6)2N(R6)N(R6)xe2x80x94, xe2x80x94C(R6)2N(R6)SO2N(R6)xe2x80x94, xe2x80x94C(R6)2N(R6)CON(R6)xe2x80x94, or xe2x80x94CON(R6)xe2x80x94;
each R6 is independently selected from hydrogen or an optionally substituted C1-4 aliphatic group, or two R6 groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring;
each R7 is independently selected from hydrogen or an optionally substituted C1-6 aliphatic group, or two R7 on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring; and
R8 is selected from xe2x80x94R, halo, xe2x80x94OR, xe2x80x94C(xe2x95x90O)R, xe2x80x94CO2R, xe2x80x94COCOR, xe2x80x94NO2, xe2x80x94CN, xe2x80x94S(O)R, xe2x80x94SO2R, xe2x80x94SR, xe2x80x94N(R4)2, xe2x80x94CON(R4)2, xe2x80x94SO2N(R4)2, xe2x80x94OC(xe2x95x90O)R, xe2x80x94N(R4)COR, xe2x80x94N(R4)CO2(optionally substituted C1-6 aliphatic), xe2x80x94N(R4)N(R4)2, xe2x80x94Cxe2x95x90NN(R4)2, xe2x80x94Cxe2x95x90Nxe2x80x94OR, xe2x80x94N(R4)CON(R4)2, xe2x80x94N(R4)SO2N(R4)2, xe2x80x94N(R4)SO2R, or xe2x80x94OC(xe2x95x90O)N(R4)2; provided that when Q is xe2x80x94NHxe2x80x94 and Ry and R8 are taken together to form a fused ring, R1 is other than a pyrazol-3-yl ring or a pyrazol-3-yl-containing bicyclic ring system.
Preferred Ry groups of formula IIb include Zxe2x80x94R3xe2x80x2 or an optionally substituted group selected from C1-6 aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, wherein Z is a methylene and R3xe2x80x2 is xe2x80x94N(R4)2, xe2x80x94OR, or an optionally substituted group selected from C1-6 aliphatic, C6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms.
Examples of preferred Ry groups include 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino such as methoxyethylamino, alkoxyalkyl such as methoxymethyl or methoxyethyl, alkyl- or dialkylamino such as ethylamino or dimethylamino, alkyl- or dialkylaminoalkoxy such as dimethylaminopropyloxy, acetamido, optionally substituted phenyl such as phenyl or halo-substituted phenyl.
The R2 and R2xe2x80x2 groups of formula IIb may be taken together to form a fused ring, thus providing a bicyclic ring system containing a pyrazole ring. Preferred fused rings include benzo, pyrido, pyrimido, and a partially unsaturated 6-membered carbocyclo ring. These are exemplified in the following formula IIb compounds having a pyrazole-containing bicyclic ring system: 
Preferred substituents on the R2/R2xe2x80x2 fused ring of formula IIb include one or more of the following: -halo, xe2x80x94N(R4)2, xe2x80x94C1-4 alkyl, xe2x80x94C1-4 haloalkyl, xe2x80x94NO2, xe2x80x94O(C1-4 alkyl), xe2x80x94CO2(C1-4 alkyl), xe2x80x94CN, xe2x80x94SO2(C1-4 alkyl), xe2x80x94SO2NH2, xe2x80x94OC(O)NH2, xe2x80x94NH2SO2(C1-4 alkyl), xe2x80x94NHC(O)(C1-4 alkyl), xe2x80x94C(O)NH2, and xe2x80x94CO(C1-4 alkyl), wherein the (C1-4 alkyl) is a straight, branched, or cyclic alkyl group. Preferably, the (C1-4 alkyl) group is methyl.
When the pyrazole ring system of formula IIb is monocyclic, preferred R2 groups include hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a C1-6 aliphatic group. Examples of such preferred R2 groups include H, methyl, ethyl, propyl, cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, and benzyloxypropyl. A preferred R2xe2x80x2 group is hydrogen.
When Ring D of formula IIb is monocyclic, preferred Ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.
When Ring D of formula IIb is bicyclic, preferred bicyclic Ring D groups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl, indolyl, isoindolyl, indolinyl, benzo[b]furyl, benzo[b]thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl.
On Ring D of formula IIb, preferred Txe2x80x94R5 or Vxe2x80x94Zxe2x80x94R5 substituents include -halo, xe2x80x94CN, xe2x80x94NO2, xe2x80x94N(R4)2, optionally substituted C1-6 aliphatic group, xe2x80x94OR, xe2x80x94C(O)R, xe2x80x94CO2R, xe2x80x94CONH(R4), xe2x80x94N(R4)COR, xe2x80x94N(R4)CO2R, xe2x80x94SO2N(R4)2, xe2x80x94N(R4)SO2R, xe2x80x94N(R6)COCH2N(R4)2, xe2x80x94N(R6)COCH2CH2N(R4)2, and xe2x80x94N(R6)COCH2CH2CH2N(R4)2, wherein R is selected from hydrogen, C1-6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring. More preferred R5 substituents include xe2x80x94Cl, xe2x80x94Br, xe2x80x94F, xe2x80x94CN, xe2x80x94CF3, xe2x80x94COOH, xe2x80x94CONHMe, xe2x80x94CONHEt, xe2x80x94NH2, xe2x80x94NHAc, xe2x80x94NHSO2Me, xe2x80x94NHSO2Et, xe2x80x94NHSO2(n-propyl), xe2x80x94NHSO2(isopropyl), xe2x80x94NHCOEt, xe2x80x94NHCOCH2NHCH3, xe2x80x94NHCOCH2N(CO2t-Bu)CH3, xe2x80x94NHCOCH2N(CH3)2, xe2x80x94NHCOCH2CH2N(CH3)2, xe2x80x94NHCOCH2CH2CH2N(CH3)2, xe2x80x94NHCO(cyclopropyl), xe2x80x94NHCO(isobutyl), xe2x80x94NHCOCH2(morpholin-4-yl), xe2x80x94NHCOCH2CH2(morpholin-4-yl), xe2x80x94NHCOCH2CH2CH2(morpholin-4-yl), xe2x80x94NHCO2(t-butyl), xe2x80x94NH(C1-4 aliphatic) such as xe2x80x94NHMe, xe2x80x94N(C1-4 aliphatic)2 such as xe2x80x94NMe2, OH, xe2x80x94O(C1-4 aliphatic) such as xe2x80x94OMe, C1-4 aliphatic such as methyl, ethyl, cyclopropyl, isopropyl, or t-butyl, and xe2x80x94CO2(C1-4 aliphatic).
When Ry and R8 are taken together to form a fused ring, preferred rings formed by Ry and R8 include 5-6 membered unsaturated or partially unsaturated rings having 0-2 heteroatoms. More preferred fused rings formed by Ry and R8 include benzo, cyclohexo, and pyrido.
Preferred R8 groups of formula IIb, when present, include R, OR, and N(R4)2. Examples of preferred R8 include methyl, ethyl, NH2, NH2CH2CH2NH, N(CH3)2CH2CH2NH, N(CH3)2CH2CH2O, (piperidin-1-yl)CH2CH2O, and NH2CH2CH2O.
Preferred formula IIb compounds have one or more, and more preferably all, of the features selected from the group consisting of:
(a) Ry is Zxe2x80x94R3xe2x80x2 or an optionally substituted group selected from C1-6 aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, wherein Z is a methylene and R3xe2x80x2 is xe2x80x94N(R4)2, xe2x80x94OR, or an optionally substituted group selected from C1-6 aliphatic, C6-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms;
(b) R1 is T-(Ring D), wherein T is a valence bond or a methylene unit;
(c) Ring D is a 5-7 membered monocyclic or an 8-10 membered bicyclic aryl or heteroaryl ring; and
(d) R2 is xe2x80x94R or xe2x80x94Txe2x80x94Wxe2x80x94R6 and R2xe2x80x2 is hydrogen, or R2 and R2xe2x80x2 are taken together to form an optionally substituted benzo ring.
More preferred compounds of formula IIb have one or more, and more preferably all, of the features selected from the group consisting of:
(a) Ry is an optionally substituted group selected from C1-6 aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl;
(b) R1 is T-(Ring D), wherein T is a valence bond, and Q is xe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94, or xe2x80x94CH2xe2x80x94;
(c) Ring D is a 5-6 membered monocyclic or an 8-10 membered bicyclic aryl or heteroaryl ring; and
(d) R2 is xe2x80x94R and R2xe2x80x2 is hydrogen, wherein R is selected from hydrogen, C1-6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring.
Even more preferred compounds of formula IIb have one or more, and more preferably all, of the features selected from the group consisting of:
(a) Ry is selected from 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino, alkoxyalkyl, alkyl- or dialkylamino, alkyl- or dialkylaminoalkoxy, acetamido, optionally substituted phenyl, or methoxymethyl, or Ry and R8 are taken together to form a 5-6 membered unsaturated or partially unsaturated ring having 0-2 heteroatoms selected from nitrogen, oxygen, or sulfur;
(b) R1 is T-(Ring D), wherein T is a valence bond and Ring D is a 5-6 membered aryl or heteroaryl ring, wherein Ring D is optionally substituted with one to two groups selected from -halo, xe2x80x94CN, xe2x80x94NO2, xe2x80x94N(R4)2, optionally substituted C1-6 aliphatic group, xe2x80x94OR, xe2x80x94CO2R, xe2x80x94CONH(R4), xe2x80x94N(R4)COR, xe2x80x94N(R4)SO2R, xe2x80x94N(R6)COCH2CH2N(R4)2, or xe2x80x94N(R6)COCH2CH2CH2N(R4)2, and Q is xe2x80x94Sxe2x80x94 or xe2x80x94NHxe2x80x94; and
(c) R2 is hydrogen or a substituted or unsubstituted C1-6 aliphatic, and L is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or xe2x80x94NHxe2x80x94.
Representative compounds of formula IIb are shown below in Table 2.
In another embodiment, this invention provides a composition comprising a compound of formula IIb and a pharmaceutically acceptable carrier.
Another aspect of this invention relates to a method of treating or preventing an Aurora-2-mediated disease with an Aurora-2 inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula IIb or a pharmaceutical composition thereof.
Another aspect of this invention relates to a method of inhibiting Aurora-2 activity in a patient, which method comprises administering to the patient a compound of formula IIb or a composition comprising said compound.
Another aspect of this invention relates to a method of treating or preventing a GSK-3-mediated disease with a GSK-3 inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula IIb or a pharmaceutical composition thereof.
One aspect of this invention relates to a method of enhancing glycogen synthesis and/or lowering blood levels of glucose in a patient in need thereof, which method comprises administering to the patient a therapeutically effective amount of a compound of formula IIb or a pharmaceutical composition thereof. This method is especially useful for diabetic patients. Another method relates to inhibiting the production of hyperphosphorylated Tau protein, which is useful in halting or slowing the progression of Alzheimer""s disease. Another method relates to inhibiting the phosphorylation of xcex2-catenin, which is useful for treating schizophrenia.
Another aspect of this invention relates to a method of inhibiting GSK-3 activity in a patient, which method comprises administering to the patient a compound of formula IIb or a composition comprising said compound.
Another method relates to inhibiting Aurora-2 or GSK-3 activity in a biological sample, which method comprises contacting the biological sample with the Aurora-2 or GSK-3 inhibitor of formula IIb, or a pharmaceutical composition thereof, in an amount effective to inhibit Aurora-2 or GSK-3.
Each of the aforementioned methods directed to the inhibition of Aurora-2 or GSK-3, or the treatment of a disease alleviated thereby, is preferably carried out with a preferred compound of formula IIb, as described above.
Another embodiment of this invention relates to compounds of formula III: 
or a pharmaceutically acceptable derivative or prodrug thereof, wherein:
Z1 is nitrogen or CR8, Z2 is nitrogen or CH, and Z3 is nitrogen or CRx, provided that one of Z1 and Z3 is nitrogen;
Rx is Txe2x80x94R3 or Lxe2x80x94Zxe2x80x94R3;
Q is selected from xe2x80x94N(R4)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or xe2x80x94CH (R6)xe2x80x94;
R1 is T-(Ring D);
Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein each substitutable ring carbon of Ring D is independently substituted by oxo, Txe2x80x94R5, or Vxe2x80x94Zxe2x80x94R5, and each substitutable ring nitrogen of Ring D is independently substituted by xe2x80x94R4;
T is a valence bond or a C1-4 alkylidene chain, wherein when Q is xe2x80x94CH(R6)xe2x80x94, a methylene unit of said C1-4 alkylidene chain is optionally replaced by xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94N(R4)xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94CONHxe2x80x94, xe2x80x94NHCOxe2x80x94, xe2x80x94SO2, xe2x80x94SO2NHxe2x80x94, xe2x80x94NHSO2xe2x80x94, xe2x80x94CO2xe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94OC(O)NHxe2x80x94, or xe2x80x94NHCO2xe2x80x94;
Z is a C1-4 alkylidene chain;
L is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94N(R6)SO2xe2x80x94, xe2x80x94SO2N(R6)xe2x80x94, xe2x80x94N(R6)xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94CO2xe2x80x94, xe2x80x94N(R6)COxe2x80x94, xe2x80x94N(R6)C(O)Oxe2x80x94, xe2x80x94N(R6)CON(R6)xe2x80x94, xe2x80x94N(R6)SO2N(R6)xe2x80x94, xe2x80x94N(R6)N(R6)xe2x80x94, xe2x80x94C(O)N(R6)xe2x80x94, xe2x80x94OC(O)N(R6)xe2x80x94, xe2x80x94C(R6)2Oxe2x80x94, xe2x80x94C(R6)2Sxe2x80x94, xe2x80x94C(R6)2SOxe2x80x94, xe2x80x94C(R6)2SO2xe2x80x94, xe2x80x94C(R6)2SO2N(R6)xe2x80x94, xe2x80x94C(R6)2N(R6)xe2x80x94, xe2x80x94C(R6)2N(R6)C(O)xe2x80x94, xe2x80x94C(R6)2N(R6)C(O)Oxe2x80x94, xe2x80x94C(R6)xe2x95x90NN(R6)xe2x80x94, xe2x80x94C(R6)xe2x95x90Nxe2x80x94Oxe2x80x94, xe2x80x94C(R6)2N(R6)N(R6)xe2x80x94, xe2x80x94C(R6)2N(R6)SO2N(R6)xe2x80x94, or xe2x80x94C(R6)2N(R6)CON(R6)xe2x80x94;
R2 and R2xe2x80x2 are independently selected from xe2x80x94R, xe2x80x94Txe2x80x94Wxe2x80x94R6, or R2 and R2xe2x80x2 are taken together with their intervening atoms to form a fused, 5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, wherein each substitutable ring carbon of said fused ring formed by R2 and R2xe2x80x2 is independently substituted by halo, oxo, xe2x80x94CN, xe2x80x94NO2, xe2x80x94R7, or xe2x80x94Vxe2x80x94R6, and each substitutable ring nitrogen of said ring formed by R2 and R2xe2x80x2 is independently substituted by R4;
R3 is selected from xe2x80x94R, -halo, xe2x80x94OR, xe2x80x94C(xe2x95x90O)R, xe2x80x94CO2R, xe2x80x94COCOR, xe2x80x94COCH2COR, xe2x80x94NO2, xe2x80x94CN, xe2x80x94S(O)R, xe2x80x94S(O)2R, xe2x80x94SR, xe2x80x94N(R4)2, xe2x80x94CON(R7)2, xe2x80x94SO2N(R7)2, xe2x80x94OC(xe2x95x90O)R, xe2x80x94N(R7)COR, xe2x80x94N(R7)CO2(C1-6 aliphatic), xe2x80x94N(R4)N(R4)2, xe2x80x94Cxe2x95x90NN(R4)2, xe2x80x94Cxe2x95x90Nxe2x80x94OR, xe2x80x94N(R7)CON(R7)2, xe2x80x94N(R7)SO2N(R7)2, xe2x80x94N(R4)SO2R, or xe2x80x94OC(xe2x95x90O)N(R7)2;
each R is independently selected from hydrogen or an optionally substituted group selected from C1-6 aliphatic, C1-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms;
each R4 is independently selected from xe2x80x94R7, xe2x80x94COR7, xe2x80x94CO2(optionally substituted C1-6 aliphatic), xe2x80x94CON(R7)2, or xe2x80x94SO2R7;
each R5 is independently selected from xe2x80x94R, halo, xe2x80x94OR, xe2x80x94C(xe2x95x90O)R, xe2x80x94CO2R, xe2x80x94COCOR, xe2x80x94NO2, xe2x80x94CN, xe2x80x94S(O)R, xe2x80x94SO2R, xe2x80x94SR, xe2x80x94N(R4)2, xe2x80x94CON(R4)2, xe2x80x94SO2N(R4)2, xe2x80x94OC(xe2x95x90O)R, xe2x80x94N(R4)COR, xe2x80x94N(R4)CO2(optionally substituted C1-6 aliphatic), xe2x80x94N(R4)N(R4)2, xe2x80x94Cxe2x95x90NN(R4)2, xe2x80x94Cxe2x95x90Nxe2x80x94OR, xe2x80x94N(R4)CON(R4)2, xe2x80x94N(R4)SO2N(R4)2, xe2x80x94N(R4)SO2R, or xe2x80x94OC(xe2x95x90O)N(R4)2;
V is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94N(R6)SO2xe2x80x94, xe2x80x94SO2N(R6)xe2x80x94, xe2x80x94N(R6)xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94CO2xe2x80x94, xe2x80x94N(R6)COxe2x80x94, xe2x80x94N(R6)C(O)Oxe2x80x94, xe2x80x94N(R6 )CON(R6)xe2x80x94, xe2x80x94N(R6)SO2N(R6)xe2x80x94, xe2x80x94N(R6)N(R6)xe2x80x94, xe2x80x94C(O)N(R6)xe2x80x94, xe2x80x94OC(O)N(R6)xe2x80x94, xe2x80x94C(R6)2Oxe2x80x94, xe2x80x94C(R6)2Sxe2x80x94, xe2x80x94C(R6)2SOxe2x80x94, xe2x80x94C(R6)2SO2xe2x80x94, xe2x80x94C(R6)2SO2N(R6)xe2x80x94, xe2x80x94C(R6)2N(R6)xe2x80x94, xe2x80x94C(R6)2N(R6)C(O)xe2x80x94, xe2x80x94C(R6)2N(R6)C(O)Oxe2x80x94, xe2x80x94C(R6)xe2x95x90NN(R6)xe2x80x94, xe2x80x94C(R6)xe2x95x90Nxe2x80x94Oxe2x80x94, xe2x80x94C(R6)2N(R6)N(R6)xe2x80x94, xe2x80x94C(R6)2N(R6)SO2N(R6)xe2x80x94, or xe2x80x94C(R6)2N(R6)CON(R6)xe2x80x94;
W is xe2x80x94C(R6)2Oxe2x80x94, xe2x80x94C(R6)2Sxe2x80x94, xe2x80x94C(R6)2SOxe2x80x94, xe2x80x94C(R6)2SO2xe2x80x94, xe2x80x94C(R6)2SO2N(R6)xe2x80x94, xe2x80x94C(R6)2N(R6)xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94CO2xe2x80x94, xe2x80x94C(R6)OC(O)xe2x80x94, xe2x80x94C(R6)OC(O)N(R6)xe2x80x94, xe2x80x94C(R6)2N(R6)COxe2x80x94, xe2x80x94C(R6)2N(R6)C(O)Oxe2x80x94, xe2x80x94C(R6)xe2x95x90NN(R6)xe2x80x94, xe2x80x94C(R6)xe2x95x90Nxe2x80x94Oxe2x80x94, xe2x80x94C(R6)2N(R6 )N(R6)xe2x80x94, xe2x80x94C(R6)2N(R6)SO2N(R6)xe2x80x94, xe2x80x94C(R6)2N(R6)CON(R6)xe2x80x94, or xe2x80x94CON(R6)xe2x80x94;
each R6 is independently selected from hydrogen or an optionally substituted C1-4 aliphatic group, or two R6 groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring;
each R7 is independently selected from hydrogen or an optionally substituted C1-6 aliphatic group, or two R7 on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring; and
R8 is selected from xe2x80x94R, halo, xe2x80x94OR, xe2x80x94C(xe2x95x90O)R, xe2x80x94CO2R, xe2x80x94COCOR, xe2x80x94NO2, xe2x80x94CN, xe2x80x94S(O)R, xe2x80x94SO2R, xe2x80x94SR, xe2x80x94N(R4)2, xe2x80x94CON(R4)2, xe2x80x94SO2N(R4)2, xe2x80x94OC(xe2x95x90O)R, xe2x80x94N(R4)COR, xe2x80x94N(R4)CO2(optionally substituted C1-6 aliphatic), xe2x80x94N(R4)N(R4)2, xe2x80x94Cxe2x95x90NN(R4)2, xe2x80x94Cxe2x95x90Nxe2x80x94OR, xe2x80x94N(R4)CON(R4)2, xe2x80x94N(R4)SO2N(R4)2, xe2x80x94N(R4)SO2R, or xe2x80x94OC(xe2x95x90O)N(R4)2.
Accordingly, the present invention relates to compounds of formula IIIa, IIIb, IIIc and IIId as shown below: 
Preferred Rx groups of formula III include Txe2x80x94R3 wherein T is a valence bond or a methylene and R3 is CN, xe2x80x94R, or xe2x80x94OR. When R3 is xe2x80x94R, preferred R3 groups include an optionally substituted group selected from C1-6 aliphatic, phenyl, or a 5-6 membered heteroaryl or heterocyclyl ring. When R3 is xe2x80x94OR, preferred R groups include an optionally substituted group C1-6 aliphatic group such as alkyl- or dialkylaminoalkyl and aminoalkyl. Examples of preferred Rx include acetamido, CN, piperidinyl, piperazinyl, phenyl, pyridinyl, imidazol-1-yl, imidazol-2-yl, cyclohexyl, cyclopropyl, methyl, ethyl, isopropyl, t-butyl, NH2CH2CH2NH, and NH2CH2CH2O.
Preferred R8 groups of formula III, when present, include R, OR, and N(R4)2. Examples of preferred R8 include methyl, ethyl, NH2, NH2CH2CH2NH, N(CH3)2CH2CH2NH, N(CH3)2CH2CH2O, (piperidin-1-yl)CH2CH2O, and NH2CH2CH2O.
The R2 and R2xe2x80x2 groups of formula III may be taken together to form a fused ring, thus providing a bicyclic ring system containing a pyrazole ring. Preferred fused rings include benzo, pyrido, pyrimido, and a partially unsaturated 6-membered carbocyclo ring. These are exemplified in the following formula III compounds having a pyrazole-containing bicyclic ring system: 
Preferred substituents on the formula III R2/R2xe2x80x2 fused ring include one or more of the following: -halo, xe2x80x94N(R4)2, xe2x80x94C1-4 alkyl, xe2x80x94C1-4 haloalkyl, xe2x80x94NO2, xe2x80x94O(C1-4 alkyl), xe2x80x94CO2(C1-4 alkyl), xe2x80x94CN, xe2x80x94SO2(C1-4 alkyl), xe2x80x94SO2NH2, xe2x80x94OC(O)NH2, xe2x80x94NH2SO2(C1-4 alkyl), xe2x80x94NHC(O)(C1-4 alkyl), xe2x80x94C(O)NH2, and xe2x80x94CO(C1-4 alkyl), wherein the (C1-4 alkyl) is a straight, branched, or cyclic alkyl group. Preferably, the (C1-4 alkyl) group is methyl.
When the pyrazole ring system of formula III is monocyclic, preferred R2 groups include hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a C1-6 aliphatic group. Examples of such preferred R2 groups include H, methyl, ethyl, propyl, cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, and benzyloxypropyl. A preferred R2xe2x80x2 group is hydrogen.
When Ring D of formula III is monocyclic, preferred Ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.
When Ring D of formula III is bicyclic, preferred bicyclic Ring D groups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl, indolyl, isoindolyl, indolinyl, benzo[b]furyl, benzo[b]thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl.
On Ring D of formula III, preferred Txe2x80x94R5 or Vxe2x80x94Zxe2x80x94R5 substituents include -halo, xe2x80x94CN, xe2x80x94NO2, xe2x80x94N(R4)2, optionally substituted C1-6 aliphatic group, xe2x80x94OR, xe2x80x94C(O)R, xe2x80x94CO2R, xe2x80x94CON(R4)2, xe2x80x94OCO(R4)2, xe2x80x94N(R4)COR, xe2x80x94N(R4)CO2R, xe2x80x94SO2N(R4)2, xe2x80x94N(R4)SO2R, xe2x80x94N(R6)COCH2N(R4)2, xe2x80x94N(R6)COCH2CH2N(R4)2, and xe2x80x94N(R6)COCH2CH2CH2N(R4)2, wherein R is selected from hydrogen, C1-6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring. More preferred R5 substituents include xe2x80x94Cl, xe2x80x94Br, xe2x80x94F, xe2x80x94CN, xe2x80x94CF3, xe2x80x94COOH, xe2x80x94CONHMe, xe2x80x94CONHEt, xe2x80x94NH2, xe2x80x94NHAc, xe2x80x94NHSO2Me, xe2x80x94NHSO2Et, xe2x80x94NHSO2(n-propyl), xe2x80x94NHSO2(isopropyl), xe2x80x94NHCOEt, xe2x80x94NHCOCH2NHCH3, xe2x80x94NHCOCH2N(CO2t-Bu)CH3, xe2x80x94NHCOCH2N(CH3)2, xe2x80x94NHCOCH2CH2N(CH3)2, xe2x80x94NHCOCH2CH2CH2N(CH3)2, xe2x80x94NHCO(cyclopropyl), xe2x80x94NHCO(isobutyl), xe2x80x94NHCOCH2(morpholin-4-yl), xe2x80x94NHCOCH2CH2(morpholin-4-yl), xe2x80x94NHCOCH2CH2CH2(morpholin-4-yl), xe2x80x94NHCO2(t-butyl), xe2x80x94NH(C1-4 aliphatic) such as xe2x80x94NHMe, xe2x80x94N(C1-4 aliphatic)2 such as xe2x80x94NMe2, OH, xe2x80x94O(C1-4 aliphatic) such as xe2x80x94OMe, C1-4 aliphatic such as methyl, ethyl, cyclopropyl, isopropyl, or t-butyl, and xe2x80x94CO2(C1-4 aliphatic).
Preferred compounds of formula IIIa, IIIb, IIIc, or IIId have one or more, and more preferably all, of the features selected from the group consisting of:
(a) Rx is hydrogen, alkyl- or dialkylamino, acetamido, or a C1-4 aliphatic group;
(b) R1 is T-(Ring D), wherein T is a valence bond or a methylene unit;
(c) Ring D is a 5-7 membered monocyclic or an 8-10 membered bicyclic aryl or heteroaryl ring; and
(d) R2 is xe2x80x94R or xe2x80x94Txe2x80x94Wxe2x80x94R6 and R2xe2x80x2 is hydrogen, or R2 and R2xe2x80x2 are taken together to form an optionally substituted benzo ring.
More preferred compounds of formula IIIa, IIIb, IIIc, or IIId have one or more, and more preferably all, of the features selected from the group consisting of:
(a) R1 is T-(Ring D), wherein T is a valence bond, and Q is xe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94, or xe2x80x94CH2xe2x80x94;
(b) Ring D is a 5-6 membered monocyclic or an 8-10 membered bicyclic aryl or heteroaryl ring; and
(c) R2 is xe2x80x94R and R2xe2x80x2 is hydrogen, wherein R is selected from hydrogen, C1-6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring.
Even more preferred compounds of formula IIIa, IIIb, IIIc, or IIId have one or more, and more preferably all, of the features selected from the group consisting of:
(a) Rx is hydrogen methyl, ethyl, propyl, cyclopropyl, isopropyl, methylamino or acetimido;
(b) R1 is T-(Ring D), wherein T is a valence bond and Ring D is a 5-6 membered aryl or heteroaryl ring, wherein Ring D is optionally substituted with one to two groups selected from -halo, xe2x80x94CN, xe2x80x94NO2, xe2x80x94N(R4)2, optionally substituted C1-6 aliphatic group, xe2x80x94OR, xe2x80x94CO2R, xe2x80x94CON(R4)2, xe2x80x94OCO(R4)2, xe2x80x94N(R4)COR, xe2x80x94N(R4)SO2R, xe2x80x94N(R6)COCH2CH2N(R4)2, or xe2x80x94N(R6)COCH2CH2CH2N(R4)2, and Q is xe2x80x94Sxe2x80x94 or xe2x80x94NHxe2x80x94; and
(c) R2 is hydrogen or a substituted or unsubstituted C1-6 aliphatic.
Representative compounds of formula III are shown below in Table 3.
In another embodiment, this invention provides a composition comprising a compound of formula III and a pharmaceutically acceptable carrier.
Another aspect of this invention relates to a method of treating or preventing an Aurora-2-mediated disease with an Aurora-2 inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula III or a pharmaceutical composition thereof.
Another aspect of this invention relates to a method of inhibiting Aurora-2 activity in a patient, which method comprises administering to the patient a compound of formula III or a composition comprising said compound.
Another aspect of this invention relates to a method of treating or preventing a GSK-3-mediated disease with a GSK-3 inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula III or a pharmaceutical composition thereof.
One aspect of this invention relates to a method of enhancing glycogen synthesis and/or lowering blood levels of glucose in a patient in need thereof, which method comprises administering to the patient a therapeutically effective amount of a compound of formula III or a pharmaceutical composition thereof. This method is especially useful for diabetic patients. Another method relates to inhibiting the production of hyperphosphorylated Tau protein, which is useful in halting or slowing the progression of Alzheimer""s disease. Another method relates to inhibiting the phosphorylation of xcex2-catenin, which is useful for treating schizophrenia.
Another aspect of this invention relates to a method of inhibiting GSK-3 activity in a patient, which method comprises administering to the patient a compound of formula III or a composition comprising said compound.
Another method relates to inhibiting Aurora-2 or GSK-3 activity in a biological sample, which method comprises contacting the biological sample with the Aurora-2 or GSK-3 inhibitor of formula III, or a pharmaceutical composition thereof, in an amount effective to inhibit Aurora-2 or GSK-3.
Each of the aforementioned methods directed to the inhibition of Aurora-2 or GSK-3, or the treatment of a disease alleviated thereby, is preferably carried out with a preferred compound of formula III as described above.
The compounds of this invention may be prepared in general by methods known to those skilled in the art for analogous compounds, as illustrated by the general Schemes I-VII. 
Scheme I above shows a general route for the preparation of compounds of formula IIb. The dichloro intermediate 1 (prepared using methods similar to those reported in J. Indian. Chem. Soc., 61, 690-693 (1984) or in J. Med. Chem., 37, 3828-3833 (1994)) is sequentially reacted with two nucleophiles: R1xe2x80x94QH to displace the chloride at position 4 to afford intermediate 2; and then 2 is treated with an aminopyrazole (or aminoindazole) to displace the chloride at position 2, using procedures similar to those described in J. Med. Chem, 38, 14, 2763-2773, (1995) to afford compounds of formula IIb. 
Scheme II above shows a general route for the preparation of compounds of formula IIb wherein Q is an N, O or S linker and Ry is a group attached to the pyrimidine core via a heteroatom. Starting material 4,6-dihydroxy-2-methylsulfanylpyrimidine (4) is prepared using procedures similar to those reported in J. Med. Chem., 27, 12, 1621-1629 (1984). Chlorination of 4 with POCl3 affords the dichloro intermediate 5. The two chlorides of 5 are sequentially displaced with the appropriate R1xe2x80x94QH, to afford compound 6, and then with Ryxe2x80x94H (amine, alcohol, or thiol) to afford compound 7 using procedures similar to those reported in U.S. Pat. No. 2,585,906. Alternatively, the order of displacement may be reversed by first displacing with Ryxe2x80x94H and then with R1xe2x80x94QH. The methyl sulfanyl group of compound 7 is then oxidized (for example, with oxone) to afford compound 8 and the resulting methylsulfonyl is finally displaced with the amino moiety of aminopyrazole (or aminoindazole) by methods substantially similar to those described above for Scheme 1 step (b) to afford compounds of formula IIb. 
Scheme III above shows a general route for the preparation of compounds of formula IIa. The three chlorides of starting material 8 are sequentially displaced with (a) the amino moiety of aminopyrazole (or aminoindazole) to afford compound 9, (b) the R1xe2x80x94QH group to afford compound 10, and (c) Ryxe2x80x94H (amine, alcohol, or thiol) using procedures similar to the ones reported in J. Indian Chem. Soc., 53, 207-208, (1976) to afford compounds of formula IIa. These three steps can also be performed in different order to afford compounds of formula IIa. 
Scheme IV above shows a general route for the preparation of compounds of formula IIIa. Treatment of 11 with aminopyrazole (or aminoindazole) to provide 12 may be performed in a manner similar to that described in Heterocycles, 51, 5, 1999, 1035-1050. The intermediate 13 is obtained by displacement with R1xe2x80x94QH in a manner similar to that described in Farmaco. Ed. Sci., 27, 1972, 591-600. For the preparation of compounds of formula IIIa where Rx is hydrogen, the chlorine may be removed by reduction. Alternatively, for the preparation of compounds of formula IIIa where Rx is other than hydrogen, the chlorine may be displaced by methods known to those skilled in the art to afford compounds with a variety of Rx substituents. 
Scheme V above shows a general route for the preparation of the compounds of formula IIIb. Displacement of the bromide with R1xe2x80x94QH to afford compound 15 may be performed in a manner similar to that described in Heterocycles, 51, 5, 1999, 1035-1050. Displacement of the chlorines may be carried out sequentially as described above. 
Scheme VI above shows a general route for the preparation of the compounds of formulae IIIc and IIId. The displacement with aminopyrazole (or aminoindazole) followed by the displacement with R1xe2x80x94QH may be performed in a manner similar to that described in Indian J. Chem. Sect. B, 29, 5, 1990, 435-439.
In order that the invention described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this invention in any manner.
The activity of the compounds as protein kinase inhibitors may be assayed in vitro, in vivo or in a cell line. In vitro assays include assays that determine inhibition of either the phosphorylation activity or ATPase activity of the activated protein kinase. Alternate in vitro assays quantitate the ability of the inhibitor to bind to the protein kinase. Inhibitor binding may be measured by radiolabelling the inhibitor prior to binding, isolating the inhibitor/protein kinase complex and determining the amount of radiolabel bound. Alternatively, inhibitor binding may be determined by running a competition experiment where new inhibitors are incubated with the protein kinase bound to known radioligands.